WO2018045104A1 - Anti-parasitic compounds - Google Patents

Anti-parasitic compounds Download PDF

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Publication number
WO2018045104A1
WO2018045104A1 PCT/US2017/049491 US2017049491W WO2018045104A1 WO 2018045104 A1 WO2018045104 A1 WO 2018045104A1 US 2017049491 W US2017049491 W US 2017049491W WO 2018045104 A1 WO2018045104 A1 WO 2018045104A1
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WIPO (PCT)
Prior art keywords
compound
optionally substituted
alkyl
represented
optionally
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PCT/US2017/049491
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French (fr)
Inventor
Karl A. Werbovetz
David W. Boykin
Abdelbasset FARAHAT
Ahmed ABDULHAMEED
Ching-Shih Chen
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Ohio State Innovation Foundation
Georgia State University Research Foundation
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Publication of WO2018045104A1 publication Critical patent/WO2018045104A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Leishmaniasis is a spectrum of disease that ranges from cutaneous lesions to life- threatening visceral infections caused by sandf!y-carried pathogenic Leishmania species, of which at least twenty are known.
  • the number of cases of visceral leishmaniasis (VL) was recently estimated as 200,000 to 400,000 per year, with about three times as many cases of cutaneous leishmaniasis (CL).
  • VL may include enlargement of the spleen and liver, anemia, and weight loss, and is usually fatal without effective drug treatment.
  • a vast majority of CL cases occur in Brazil and Peru along with several countries of the Middle East, including Afghanistan, Iran, Iraq, and Republic.
  • the sandfly bite typically progresses from a papule to a nodule to an ulcerative lesion.
  • Such lesions may self-cure over a period of 2-15 months but may result in a persistent and potentially disfiguring scar.
  • Other manifestations may occur, including diffuse CL (disseminated nodules), leishmaniasis recidivans (recurring infection near a healed lesion), and mucosal leishmaniasis (disfiguring lesions in the mucous membranes of the nose and mouth).
  • Liposomal AmB is relatively expensive, limiting its widespread use in developing countries, and is also less effective against Brazilian and East African strains compared to India strains.
  • Paromomycin is inexpensive and effective against Indian VL but is less useful against East African VL.
  • Miltefosine is orally available and useful against Indian VL, but is teratogenic in lab animals. A high relapse rate was recently reported for treating VL with miltefosine in Nepal.
  • Injectable antimonials form the basis of most treatment regimens for VL in the New World and are also typically used in the therapy of cutaneous leishmaniasis (CL), either by parenteral or intralesional injection.
  • Miltefosine is recommended for treating CL infections caused by only L. guyanensis, L. panamensis, and L. mexicana, while parenteral pentamidine is a drug of choice for CL caused by L. guyanensis.
  • Topical paromomycin is less costly and displays fewer side effects than antimonials but is inferior to these drugs against CL in both the Old World and the New World.
  • azole antifungal drugs ketoconazole, fluconazole, and itraconazole have all been evaluated in clinical trials against leishmaniasis. While these azoles are orally available and have shown clinical activity against VL and CL, they lack consistent efficacy.
  • Arylimidamides (AT As) possess in vitro anti-leishmanial activity and in vivo efficacy in rodent VL models, but higher activity and efficacy is desirable.
  • Studies have shown efficacy for combined application of the AIA DB766 and the azole antifungal posaconazole in vitro.
  • Some anti-leishmanial combinations have been explored in clinical trials, and miltefosine and AmB may be synergistic in mice when given together. However, miltefosine has significant weaknesses, and no oral anti-leishmanial drug combinations exist.
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R 1 and R may independently be H, optionally substituted Ci-C , alkyl, or optionally substituted C Ce cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloaikyi, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted Ci-Cu alkyl or optionally substituted C2-C 14 alkenyl, e.g., optionally substituted C-.-Cio alkyl or optionally substituted C Cjo alkenyl, or optionally substituted Ci-Cg alkyl or optionally substituted C 2 -Cs alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen -containing heteroaromatic ring comprising ! , 2, or 3 ring heteroatoms.
  • the compound represented by Structural Formula (la) may exclude free- base Compounds la-f:
  • Het 1 may be an optionally substituted, nitrogen- containing heteroaryl.
  • R ! and R may independently be H, optionally substituted Cr-C 6 alkyl, or optionally substituted C3-C6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heteiOcydoaikyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted Ci-Cio alkyl or optionally substituted C 2 -Cio alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • the compound represented by Structural Formula (I) may exclude free-base Compounds la-f:
  • a method of anti -parasitic treatment in a subject in need thereof may include providing the subject, the subject being infected by a parasite or at risk of infection by the parasite.
  • the method may include administering a compound to the subject in an amount effective to mitigate infection by the parasite in the subject.
  • the compound may be represented by Structural Formula (la):
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted Ci-Ce alkyi, or optionally substituted t C , cycloalkvl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkvl, heterocvcloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted Cj-C-, 4 alkyi or optionally substituted C?-C j4 alkenyl, e.g., optionally substituted C-.-Cio alkyi or optionally substituted C 2 -Cio alkenyl, or optionally substituted Ci-Cg alkyi or optionally substituted C2-C8 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 nng heteroatoms.
  • a method of anti-parasitic treatment in a subject in need thereof may include providing the subject, the subject being infected by a parasite or at risk of infection by the parasite.
  • the method may include administering a compound to the subject in an amount effective to mitigate infection by the parasite in the subject.
  • the compound may be represented by Structural Formula (I):
  • Het 1 may be an optionally substituted, nitrogen- containing heteroaryl.
  • R 1 and R may independently be H, optionally substituted Ci-Ce alkyi, or optionally substituted C3-C6 cycloalkvl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings.
  • Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycioaikyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted Ci-C io alkyi or optionally substituted C 2 -C 10 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • a pharmaceutical composition may include a pharmaceutically acceptable excipient and a compound represented by Structural Formula (la):
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R 1 and R z may independently be H, optionally substituted Ci-Ce alkyi, or optionally substituted t C , cycloalkvl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocvcloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted Cj -C-, 4 alkyi or optionally substituted C?-C j4 alkenyl, e.g., optionally substituted C i -Cio alkyl or optionally substituted C 2 -C lo alkenyl, or optionally substituted Ci-Cg alkyl or optionally substituted C 2 -Cg alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1 , 2, or 3 ring heteroatoms.
  • a pharmaceutical composition may include a pharmaceutically acceptable excipient and a compound represented by Structural Formula Structural Formula (I):
  • Het 1 may be an optionally substituted, nitrogen- containing heteroaryl.
  • R ! and R may independently be H, optionally substituted Ci-C , alkyl, or optionally substituted C3-C6 cvcloalkvl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings.
  • Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroar ⁇ '!.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted Ci-C-.o alkyl or optionally substituted C 2 -C 10 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen -containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • kits for anti-parasite treatment of a subject in need thereof may include a compound represented by Structural Formula (I):
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R f and R 2 may independently be H, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be (), S, amide, or a bond.
  • Y may be optionally substituted C1-C 14 alkyl or optionally substituted C2-C14 alkenyl, e.g., optionally substituted C1-C10 alkyl or optionally substituted C Cjo alkenyl, or optionally substituted Ci-Cs alkyl or optionally substituted CVCg alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1 , 2, or 3 ring heteroatoms.
  • kits for anti -parasite treatment of a subject in need thereof may include a compound represented by Structural Formula (1):
  • Het 1 may be an optionally substituted, nitrogen-containing heieroaiyl
  • R 1 and R 2 may independently be H, optionally substituted Ci-C f , alky], or optionally substituted C3-C6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C1-C10 alkyl or optionally substituted C Cio alkenyi.
  • Met 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • the kit may include instructions. The instructions may direct a user to provide the subject, the subject being infected by a parasite or at risk of infection by the parasite. The instructions may direct a user to administer the compound or the pharmaceutical composition to the subject in an amount effective to mitigate infection by the parasite in the subject.
  • FIG. 1 (PRIOR ART) depicts structures of various known compounds.
  • FIG. 2A is a synthetic scheme for various phenoxyalkyl linker anti-parasitic compounds.
  • FIG. 2B is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted meta to the arylimidamide group.
  • FIG. 2C is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted orlho to the arylimidamide group.
  • FIG. 21 is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted with pyrrole.
  • FIG. 3A is a synthetic scheme for various phenyl-unsubstituted diphenylfuran alkyloxy linker hybrid compounds.
  • FIG. 3B is a synthetic scheme for various phenyl substituted diphenylfuran alkyloxy linker hybrid compounds.
  • FIG. 3C is a synthetic scheme for various phenyl substituted diphenylfuran alkyloxy linker hybrid compounds.
  • FIG. 3D is a prophetic synthetic scheme for various diphenylfuran alkyloxy linker hybrid compounds.
  • FIG. 4 is a prophetic synthetic scheme for various alkyl amide linker hybrid compounds.
  • FIG. SA is a prophetic synthetic scheme for various phenylalkyl linker hybrid compounds 8a and 8b.
  • FIG. SB is a synthetic scheme for various phenylalkyl linker hybrid compounds.
  • FIG. 6A is a synthetic scheme for various unsubstituted and substituted biphenyl linker a ti -parasitic compounds.
  • FIG. 63B is a synthetic scheme for various substituted biphenyl tinker antiparasitic compounds.
  • FIG. 6C is a synthetic scheme for various substituted biphenyl linker antiparasitic compounds.
  • FIG. 6D is a synthetic scheme for various substituted biphenyl linker antiparasitic compounds.
  • FIG. 7A is a synthetic scheme for various phenyl-piperazinyl-phenyl linker antiparasitic compounds.
  • FIG. 7B is a synthetic scheme for various phenyl-piperazinyl linker anti-parasitic compounds.
  • FIG. 8A is a table reciting IC50 values of various phenoxyalkyl linker compounds against L. donovani, CC50 values against J774 macrophages, and CC50 values against HepG2.
  • FIG. 8B is a table reciting IC50 values of various diphenyifuran alkyloxy linker compounds against L. donovani, CC5 0 values against J774 macrophages, and CC50 values against HepG2.
  • FIG. 8C is a table reciting IC5 0 values of various biphenyl alkyloxy linker compounds against L. donovani, CC5 0 values against J774 macrophages, and CC5 0 values against HepG2.
  • FIG. 8D is a table reciting IC5 0 values of various piperazinyi linker compounds against L. donovani and CC5 0 values against J774 macrophages.
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryi.
  • R f and R 2 may independently be H, optionally substituted CrC 6 alkyl, or optionally substituted C3-C6 cycioalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycioalkyl, heterocvcloalkyl, and heteroaryi.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C1-C 14 alkyl or optionally substituted C 2 -C 14 alkenyl, e.g., optionally substituted Ci-Cio alkyl or optionally substituted C 2 -Cio alkenyl, or optionally substituted Cj-Cg alkyl or optionally substituted CVCg alkenyl.
  • Met 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1 , 2, or 3 ring heteroatoms.
  • a compound is provided, represented by Structural
  • Het 1 may be an optionally substituted, nitrogen- containing heteroar ⁇ '!.
  • R ! and R may independently be H, optionally substituted Ci-CV, alkyl, or optionally substituted C3-C6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, lieterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted CI-CH alkyl or optionally substituted C2-C14 alkenyl, e.g., optionally substituted C 1 -C10 alkyl or optionally substituted C 2 -C 10 alkenyl , or optionally substituted Cj-Cg alkyl or optionally substituted C 2 -Cg alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • (I) may exclude certain compounds.
  • the compound represented by Structural Formula (la) or (I) may exclude free-base (neutral or non-salt) forms of Compounds la-f, wherein: Het 3 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; X is O; Y is unbranched, unsubstituted C 2 -C 4 alkyl; and Het 2 is unsubstituted imidazole- 1 -yl or unsubstituted 1 , 2, 4 triazol-2-yl:
  • (I) may include pharmaceutically acceptable salts of Compounds la-f.
  • the compound represented by Structural Formula (la) or (I) may exclude free-base forms of Compounds la-f and pharmaceutically acceptable salts of Compounds la-f.
  • the compound represented by Structural Formula (la) or (I) may exclude protonated forms of Compounds la-f.
  • (I) may exclude compounds wherem Het 5 is one of unsubstituted pyridyl and pyrid-2-yl substituted with methyl or ethyl, for example, when: R ! and R 2 are each H; X is O; Y is unbranched, unsubstituted C 2 -C 4 alky] ; and Het 2 is unsubstituted imidazole- ! -yl or unsubstituted 1 ,2,4-triazol-2-yl.
  • the compound represented by Structural Formula (la) or (1) may exclude compounds wherein one of R 1 and R 2 is H and the other is methyl or ethyl, for example, when: Het 1 is unsubstituted pyrid-2-yl; X is O; Y is unbranched, unsubstituted C 2 - C 3 ⁇ 4 alkyl; and Het" is unsubstituted imidazole- 1 -yl or unsubstituted l,2,4-triazol-2-yl.
  • the compound represented by Structural Formula (la) or (I) may exclude compounds wherem X is S, for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; Y is unbranched, unsubstituted C 2 -C 4 alkyl; and Het 2 is unsubstituted imidazole-l -yl or unsubstituted l,2,4-triazoi-2-yl.
  • the compound represented by Structural Formula (la) or (1) may exclude compounds wherein Y is C 2 -C 4 alkyl substituted with methyl or ethyl, unsubstituted or methyl substituted C1-C5 alkyl, or unsubstituted Ci-Ce alkyl, for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; X is O; and Het 2 is unsubstituted imidazole-l-yl or unsubstituted l ,2,4-triazol-2-yl.
  • the compound represented by Structural Formula (la) or (I) may exclude compounds wherein Het 2 is one of: methyl or ethyl substituted imidazole-l -yl; unsubstituted imidazolyl; methyl or ethyl substituted imidazolyl; methyl or ethyl substituted l,2,4-triazol-2-yl; unsubstituted 1 ,2,4-triazolyl; methyl or ethyl substituted 1,2,4-triazolyl; unsubstituted triazolyl; and methyl or ethyl substituted triazolyl; for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; X is O; and Y is unbranched, unsubstituted C 2 -C 4 alkyl.
  • Het 1 may be optionally substituted pyridyl, pyrazinyl, pyrimidinyl, or pyridizinyl.
  • Het 1 may be optionally substituted pyridyl.
  • the compound may be represented by Structural Formula
  • each ring in the optionally substituted linking moiety- represented by A may be independently and optionally substituted by one or more of: hydroxy, halo, and C] ⁇ C t , alkoxy.
  • A may include an optionally substituted heteroaryl or optionally substituted heterocycloalkyl ring.
  • A may include an optionally substituted, oxygen-containing, heteroaryl or heterocycloalkyl ring.
  • A may include an optionally substituted furanyi or optionally substituted ietrahydrofuranyl ring.
  • A may include optionally substituted 2,5-furanyl.
  • A may include one or two optionally substituted phenyl ring
  • A may include optionally substituted 1.4-phenyl.
  • A may be optionally substituted 1 ,4-phenyl.
  • A may be optionally substi luted pheny 1 -heteroaryl -phenyl .
  • the compound of Structural Formula III may be represented by one of Structural Formulas Illa)-(IIIf):
  • Z, Z 1 , and Z 2 are each independently CH or N, n may be 1-14, e.g., 1-10, and R J may represent H, halogen, optionally halogenated Ci-C f , alkyl, or optionally halogenated Ci-C f , alkoxy.
  • the compound may be, for example, represented by Structural Formula above, e.g., compound 14
  • the compound may be represented by Structural Formula
  • each R J may independently represent H, halogen, optionally halogenated Cj-C 6 alkyl optionally halogenated Ci-C 6 alkoxy.
  • the compound may be represented by Structural Formula (V):
  • Y may include at least 4 linking atoms between X and
  • X may be O or a bond and Y may be Ci-Cw, e.g.. Ci-Cio alkyl optionally substituted with one or more of: optionally halogenated C-.-Cs alkyl and optionally halogenated aryl.
  • the compound may be represented by one of Structural Formulas
  • Z. Z and Z 2 are each independently CH or .
  • n may be 1-14, e.g.. 1-10, and R* may represent H, halogen, optionally halogenated CrC 6 alkyl, or optionally halogenated Ci-C 6 alkoxy.
  • the compound may be represented by
  • the compoimd may be one of Compounds 2a-2h:
  • the compound may be, for example, represented by Stmctural Formula (Vd) above, e.g., one of compounds 13a-13c:
  • R 4 may be H, optionally halogenated CVCJO alkyl, or optionally halogenated aryl.
  • the compound may be represented by Structural Formula (Vlb):
  • Het 2 may include an optionally substituted one of: pyrrole, diazole, thiadiazole, oxadiazole, and tnazole.
  • Het 2 may be optionally substituted imidazole or optionally substituted 1, 2, 4 triazole,
  • the compound may be represented by Structural Formula
  • each R 5 may independently be H, halogen, C] ⁇ C 4 alkyl, or C1-C4 alkoxy; and R 6 may be H, optionally halogenated C-.-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl
  • the compound may be one of Compounds 5a-5f:
  • the compound may be represented by Structural Formula
  • each R s may independently be H, halogen, C 1 -C alkyl. or C 1 -C4 alkoxy; and R" may ⁇ be H, optionally haiogenated CrC 6 alkyl, optionally halogenated phenyl, or optionally halogenated bi phenyl.
  • the compound may be one of Compounds 6a-6f:
  • the compound may be represented by Structural Formula
  • each R s may independently be H, halogen, C C 4 alkyl, or C1-C4 alkoxy; and R" may ⁇ be H. optionally halogenated C;-C 6 alkyl, optionally halogenated phenyl, or optionally halogenaied biphenyl.
  • the compound may be one of Compounds 7a-7f:
  • the compound may be represented by Structural Formula
  • each R 5 may independently be H, halogen, C1-C4 alkyl, or C1-C4 alkoxy; and R 6 may be H, optionally halogenated C : -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated bi phenyl,
  • the compound may be represented by Structural Formula
  • R s may independently be H, halogen, CrC 4 alkyl, or C1-C4 alkoxy; and R 6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenated phenyl, or optionally halogenated bi phenyl .
  • A may be phenyl and X may be a bond.
  • the compound may be represented by Structural Formula (XIII):
  • Z may be CH or N; and si may be an integer from 1 to 10.
  • the compound may be one of Compounds 8a-8b:
  • A may be a bond.
  • the compound may be represented by Structural Formula (la) or (I).
  • Z may be CH or N; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 9a-9d, e.g., 9a-9c:
  • A may be optionally substituted biphenyl.
  • the compound may be represented by Structural Formula XV):
  • Z, Z and Z 1 are each independently CH or N, n may be 1-14, e.g., 1- 10, and R 3 may- represent H, halogen, optionally halogenated Cj-C 6 alkyl, or optionally halogenated Cj-C 6 alkoxy.
  • the compound may be one of Compounds 10a ⁇ 10n:
  • A may be optionally substituted phenyl-piperazinyl-phenyl.
  • the compound may be represented by one of Structural Formulas XVI) and (XVII):
  • the compounds may be represented by one of (XVIa)-(XVIb):
  • n may be 1- 14, e.g., 1-10, and R 3 may- represent H, halogen, optionally halogenated Cj -C 6 alkyl, or optionally halogenated Cj -C 6 alkoxy .
  • the compound may be one of Compounds lla-l ld:
  • the compounds may be represented by one of (XVIIa)-(XVIIb):
  • Z, Z 1 , and Z 2 are each independently CH or N, n may be 1-14, e.g., 1-10, and R J may represent H, halogen, optionally halogenated Ci ⁇ C 6 alk l, or optionally halogenated Ci ⁇ C 6 alkoxy.
  • the compound may be Compound 12a:
  • a method of anti-parasitic treatment may include providing a subject that is infected by or at risk of infection by a parasite.
  • the method may include administering a compound to the subject in an amount effective to mitigate infection by the parasite in the subject.
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R 1 and R z may independently be H, optionally substituted Ci-Ce alkyl, or optionally substituted C C , cycloalkvl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkvl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C1-C14 alkyl or optionally substituted C2-C 14 alkenyl, e.g., optionally substituted C-.-Cio alkyl or optionally substituted C2-C 30 alkenyl, or optionally substituted Ci-Cg alkyl or optionally substituted C2-C8 alkenyl.
  • Het 2 may be an
  • the compound of the method may be represented by Structural Formula (1):
  • Het 3 may be an optionally substituted, nitrogen- containing heteroaryi.
  • R 1 and R 2 may independently be H, optionally substituted Cj-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.
  • A may be a bond or an optionally substituted Unking moiety comprising 1, 2, or 3 rings.
  • Each ring in the optionally substituted linking moiety may independently be one of: ary , cycloalkyl, heterocycloalkyl, and heteroaryi.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted Ci-Cu alkyl or optionally substituted C2-C 14 alkenyl, e.g., optionally substituted Ci-Cio alkyl or optionally substituted C 2 -C 10 alkenyl, or optionally substituted Ci ⁇ Cg alkyl or optionally substituted C 2 -Cg alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising I, 2, or 3 ring heteroatoms.
  • the method may include administering the compound represented by Structural Formula (la) or (I) in the form of any pharmaceutical composition described herein.
  • the compound represented by Structural Formula (la) or (I) may exclude free-base forms of Compounds la-f.
  • the compound represented by Structural Formula (la) or (I) may exclude protonated forms of Compounds la-f.
  • the subject may be infected by the parasite, and the method may include administering the compound to the subject in an amount effective to mitigate one or more symptoms of infection by the parasite in the subject.
  • the subject may be at risk of infection by the parasite.
  • the method may include administering the compound to the subject in an amount effective to mitigate infection or reinfection of the subject by the parasite.
  • the parasite may be a kinetoplastid.
  • the parasite may belong to the genus Leishmcmia.
  • the Leishmama parasite may be, for example, one of: L. aethiopica, L. amazonensis, L. arabica, L. archibaldi, L. aristedesi, L. Viannia, L. braziliensis, L. chagasi, L, colombiensis, L. deanei, L. donovani, L. enriettii, L, eq atorensis, L. forattinii, L. garnhami, L. gerbili, L.
  • the subject may suffer from or may be at risk of one or more of: cutaneous leishmaniasis, mucocutaneous leishmaniasis, and visceral leishmaniasis.
  • the subject may be a human, dog, cat, cow, horse, sheep, pig, bird, amphibian, or fish, e.g., a mammal such as a human.
  • the parasite may belong to the genus Trypanosoma.
  • Trypanosoma parasite may be, for example, one of: T. amhystomae, T. avium, T. boissoni, T. brucei, T. cruzi, T, congolense, T, equinum, T eqwperdum, T. evansi, T. everetti, T. hosei, T. irwini, T. lewisi, T. melophagium, T. paddae, T. parroti, T. percae, T. rangeli, T. rotatorium, T. rugosae, T. ser genii, T. simiae, T. simper cae, T. suis, T. theileri, T.
  • the subject may suffer from or may be at risk of one or more of: Africa trypanosomiasis, sleeping sickness, Chagas disease, nagana, and surra.
  • the subject may be a human, dog, cat, cow, horse, sheep, pig, bird, amphibian, or fish, e.g., a mammal such as a human.
  • the compound represented by Structural Formula (la) or (I) when the parasite is L. amazonensis, the compound represented by Structural Formula (la) or (I) may exclude free-base forms of Compounds la-f.
  • the compound represented by Structural Formula (la) or (I) may exclude protonated forms of Compounds la-f.
  • the compound represented by Structural Formula (la) or (I) in the method may exclude each of free-base Compounds la-f when the parasite is one of L. donovani, L. amazonensis, and L. major.
  • the method may exclude each of free-base Compounds la-f when the parasite is of the genus Leishmania, for example, one of: L.
  • the method may exclude each of free-base Compounds la-f when the subject suffers from visceral leishmaniasis.
  • Formula (la) or (I) may exclude each of free-base Compounds la-f when the parasite is T. brucei or T. cruzi.
  • the method may exclude each of free-base Compounds la-f when the parasite is of the genus Trypanosoma, for example, one of: T. ambysiomae, T. avium, T. boissoni, T. brucei, T. cruzi, T. congolense, T. equinum, T. equiperdurn, T. evansi, T. everetti, T. hosei, T. irwini, T. lewisi, T. melophagium, T. paddae, T. parroti, T.
  • each of the preceding parasite-based exclusions may be independently applied in corabinaiion with any of the various embodiments described herein as excluding certain compounds represented by Structural Formula (la) or (1).
  • the method may incorporate any of the various embodiments described herein for excluding certain compounds represented by Structural Formula (la) or (I).
  • the compound represented by Structural Formula (la) or (I) may exclude free-base (neutral or non-salt) forms of Compounds la-f.
  • the compound represented by Structural Formula (la) or (I) may include pharmaceutically acceptable salts of Compounds la-f.
  • the compound represented by Structural Formula (la) or (I) may exclude free-base forms of Compounds la-f and pharmaceutically acceptable salts of Compounds la-f.
  • the compound represented by Structural Formula (la) or (I) may exclude protonated forms of Compounds la-f.
  • the compound may include any aspect of the compounds represented by Structural Formulas (la) or (I) as described herein.
  • the compounds of the method may be represented by, as described herein, any one of, or any group of, Structural Formulas: (1), (la), (II), (III), (Ilia), (1Mb), (Illc), (Hid), (Hie), (Illfj, (IV), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Via), (VIb), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVa), (XVb), (XVc), (XVI), (XVIa), (XVIb), (XVII), (XVIIa), and (XVIIb).
  • the compound may be any one of, or any group of, as described herein, Compounds: la-lv; 2a-2h: 3a-3g; 4a-4m; 5a-5f; 6a-6f; 7a-7f; 8a-8b; 9a-9d; lOa-lOe; l la-lld; 12a; 13a- 13c; and 14a.
  • Structural Formulas (la) or (I) may exclude compounds wherein Het 1 is one of unsubstituted pyridyl and pyrid-2-yl substituted with methyl or ethyl, for example, when: R 1 and R are each H; X is O; Y is unhranched, unsubstituted C2-C10 alkyl; and Het 2 is unsubstituted imidazole- 1 -yl or unsubstituted 1, 2, 4 triazol-2-yl.
  • the compound represented by Structural Formula (la) or (I) may exclude compounds wherein one of R 3 and R 2 is H and the other is methyl or ethyl, for example, when: Het 1 is unsubstituted pyrid-2-yl; X is O; Y is unbranched, unsubstituted C2-C10 alkyl; and Hef is unsubstituted imidazole-l-yl or unsubstituted 1 , 2, 4 triazol-2-yl.
  • the compound represented by Structural Formula (la) or (I) may exclude compounds wherein X is S, for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; Y is unbranched, un substituted C 2 -C 10 alkyl; and Het 2 is unsubstituted imidazole-l-yl or unsubstituted 1 , 2, 4 triazol-2-yl.
  • the compound represented by Structural Formula (la) or (1) may exclude compounds wherein Y is C2-C4 alkyl substituted with methyl or ethyl, unsubstituted or methyl substituted C1-C5 alkyl, or unsubstituted Ci-Ce alkyl, for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; X is O; and Het 2 is unsubstituted imidazole-l -yl or unsubstituted 1, 2, 4 triazol-2-yl.
  • the compoimd represented by Structural Formula (la) or (I) may exclude compounds wherein Het 2 is one of: methyl or ethyl substituted imidazole-l-yl; unsubstituted imidazolyl; methyl or ethyl substituted imidazolyl; methyl or ethyl substituted l,-2,-4-triazol-2- yl; unsubstituted 1 ,-2,-4-triazolyl; methyl or ethyl substituted 1,-2,-4-triazolyl; unsubstituted triazolyl; and methyl or ethyl substituted triazolyl ; for example, when: Het 1 is unsubstituted pyrid-2-yl: R 1 and R are each H: X is O; and Y is unbranched, unsubstituted C2-C4 alkyl.
  • Het 1 may be optionally substituted pyridyl, pyrazinyl, pyrimidinyl, or pyndizinyl.
  • Het 1 may be optionally substituted pyridyl.
  • the compound of the method may be represented by Structural Formula (II).
  • the compound of the method may be represented by Structural Formula (III).
  • Y may include at least 4 linking atoms between X and Het 2 .
  • X may be O or a bond and Y may be C1-C14, e.g., C1-C10 alkyl optionally substituted with one or more of: optionally halogenated Cj-Cs alkyl and optionally halogenated aryl.
  • the compound may be one of Compounds la-n.
  • the compound of the method may be represented by any of Structural Formulas (Ilia), (IHb), (IIIc), (Hid), (Hie), and (Hlf), wherein Z, Z and 7 ' may be each independently CH or N, n may be 1-14, and R 3 may be H, halogen, optionally halogenated CVC 6 alkyl, or optionally halogenated C-. -Ce alkoxy.
  • the compound of the method may be any one of Compounds la-lv.
  • the compound of the method may be any one of Compounds la-ln.
  • each ring in the optionally substituted linking moiety represented by A may be independently and optionally substituted by one or more of: hydroxy, halo, and Ci-C io , e.g., Ci-Cs alkoxy.
  • A may include an optionally substituted heteroaryl or optionally substituted heterocycloalkyl ring.
  • A may include an optionally substituted, oxygen-containing, heteroaryl or heterocycloalkyl ring.
  • A may include an optionally substituted furanyl or optionally substituted tetrahydrofuranyl ring.
  • A may include optionally substituted 2,5-furanyl.
  • A may include one or two optionally substituted phenyl rings.
  • A may include optionally substituted 1 ,4-phenyl.
  • A may be optionally substituted 1,4-phenyl.
  • A may ⁇ be optionally substituted phenyl-heteroaryl-phenyl.
  • the compound may be represented by
  • Structural Formula (IV) wherein each R 3 may independently represent H, halogen, optionally halogenated Ci-C 6 alkyl, or optionally halogenated Ci-C 6 alkoxy.
  • the compound may be represented by Structural Formula (V).
  • the compound of the method may be represented by any of Structural Formulas (V), (Va), (Vb), (Vc), (Vd), and (Ve), wherein Z, Z 1 , and Z 2 may be each independently CH or N, n may be 1 -14, and R 3 may be H, halogen, optionally halogenated Ci-C , alkyl, or optionally halogenated C i-Cr, alkoxy,
  • the compound may be represented by
  • the compound may be represented by Structural Formula (VIb), 10084]
  • Het 2 may include an optionally substituted one of: pyrrole, diazole, thiadiazole, oxadiazole, and triazole.
  • Het 2 may be optionally substituted imidazole or optionally substituted 1 , 2, 4 triazole.
  • the compound may be represented by Structural Formula (VII), wherein: Z may be CH or N; each R 3 may independently be H, halogen, optionally halogenated Ci-C 6 alkyl, or optionally halogenated C1-C0 alkoxy; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 2a ⁇ 2g.
  • the compound may be, for example, one of Compounds 3a- 3g.
  • the compound may be, for example, one of Compounds 4a-4m, e.g., 4a-4i.
  • the compound may be, for example, one of Compounds 13a-13c.
  • the compound may be represented by
  • each R 3 may independently be H, halogen, Ci ⁇ C4 alkyl, or C j- 1 4 alkoxy
  • R 6 may be H, optionally halogenated CrC 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be one of Compounds 5a-5f.
  • the compound may be represented by Structural Formula (IX), wherein: each R 5 may independently be H, halogen, Cj - alkyl, or Cj - alkoxy; and R 6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl .
  • the compound may be one of Compounds 6a-5f.
  • the compound may be represented by Structural Formula (X) wherein: each R 5 may independently be H, halogen, Ci ⁇ C4 alkyl, or C1-C4 alkoxy; and ll 6 may be H, optionally halogenated CrC 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be one of Compounds 7a-7f.
  • the compound may be represented by
  • each R s may independently be H, halogen, C1-C4 alkyl, or Ci- C4 alkoxy; and R 6 may be H, optionally halogenated i-C alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be represented by
  • each R s may independently be H, halogen, C1-C4 alkyl, or Ci- C4 alkoxy; and R 6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenaied phenyl, or optionally halogenated biphenyl.
  • R s may independently be H, halogen, C1-C4 alkyl, or Ci- C4 alkoxy; and R 6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenaied phenyl, or optionally halogenated biphenyl.
  • the compound may be represented by Structural Formula (XIII), wherein Z may be CH or N; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 8a-8b.
  • the compound may be represented by
  • the compound may be represented by Structural Formula (XIV), wherein Z may be CH or N; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 9a-9d, for example, 9a-9c.
  • the compound may be represented by
  • Stmctural Formula (XV) wherein Z, Z f , and Z 2 may be each independently CH or , n may be 1-14, and R 3 may be H, halogen, optionally halogenated Ci-Ce alkyl, or optionally halogenated CrCe alkoxy.
  • the compound may be represented by one of Structural Formulas (XVa)-(XVc).
  • the compound may be one of Compounds 10a- 10 ⁇ .
  • the compound may be represented by one of Structural Formulas (XVI) and (XVII), wherein Z, Z and Z 2 may be each independently CH or N, n may be 1-14, and R' may be H, halogen, optionally halogenated Ci-Cr, alkyl, or optionally halogenated Ci-C 6 alkoxy.
  • the compound may be represented by one of Structural Formulas (XVIa)-(XVIb), e.g., the compound may be one of Compounds lla-lld.
  • a pharmaceutical composition may include a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition may include a compound represented by
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C1-C5 alkyl, or optionally substituted C3-C6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising I, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycioalkyi, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C 1-C 14 alkyl or optionally substituted C 2 -C 14 alkenyl, e.g., optionally substituted Cj-Cio alkyl or optionally substituted C 2 -Cio alkenyl, or optionally substituted Cj-Cg alkyl or optionally substituted C?-CB alkenyl.
  • Met 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • the pharmaceutical composition may include a compound represented by
  • Het 1 may be an optionally substituted, nitrogen- containing heteroaryl.
  • R 1 and R z may independently be H, optionally substituted C]-Ce alkyl, or optionally substituted C3-CV, cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C1-C14, e.g., Cj-Cio alkyl or optionally substituted C2-C 14, e.g., Cj-C-.o alkenyi.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1 , 2, or 3 ring heteroatoms.
  • the compound represented by Structural Formula (la) or (1) may include one of Compounds la-f.
  • each of Compounds la-f may be in the form of a solid.
  • each of Compounds la ⁇ f may be in the form of a pharmaceutically acceptable salt.
  • at least a portion of the pharmaceutically acceptable carrier or excipient may be in the form of a solid or gel.
  • the pharmaceutical composition may be configured for administration in unit dosage form.
  • the pharmaceutical composition may be configured for administration in the form of one of: a tablet; a capsule; a lozenge; a cream, a spray, a transdermal patch, an aerosol, a suppository, a depot preparation; a suture that is coated or impregnated with one of Compounds la-f; a bandage that is coated or impregnated with one of Compounds la-f; a medical device that is coated or impregnated with one of Compounds la-f; and the like.
  • pharmaceutically acceptable salts of Compounds la- If are included.
  • free-base (neutral) Compounds la-f may be excluded.
  • protonated forms of Compounds la-lf may be excluded.
  • the pharmaceutical composition may incorporate any of the various embodiments described herein for excluding certain compounds represented by Structural Formula (la) or (I).
  • the compound represented by Structural Formula (la) or (I) may exclude free-base (neutral or non-salt) forms of Compounds la-f.
  • the compound represented by Structural Formula (la) or (I) may include pharmaceutically acceptable salts of Compounds la-f.
  • the compound represented by Structural Formula (la) or (I) may exclude free-base forms of Compounds la-f and pharmaceutically acceptable salts of Compounds la-f.
  • the compound represented by Stmctural Formula (la) or (I) may exclude protonated forms of Compounds la-f.
  • the compound may include any aspect of the compounds represented by Structural Formulas (la) or (I) as described herein.
  • the compounds of the pharmaceutical composition may be represented by, as described herein, any one of, or any group of, Structural Formulas: (1), (la), (II), (HI), (Ilia), (IIIf>), (IIIc), (Hid), (Hie), (Illi), (IV), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Via), (VIb), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVa), (XVb), (XVc), (XVI), (XVIa), (XVifo), (XVII), (XVIIa), and (XVIIb).
  • the compound may be any one of, or any group of, as described herein, Compounds: la-lv; 2a-2h; 3a-3g; 4a-4m; 5a-5f; 6a-6f; 7a-7f; 8a-8b; 9a-9d; lOa-lOn; lla-lld; 12a; 13a-13c; and 14a.
  • the compounds represented by Structural Formulas (la) or (I) may exclude compounds wherein Het 5 is one of unsubstituted pyridyl and pyrid-2-yl substituted with methyl or ethyl, for example, when: R 1 and R 2 are each H; X is O; Y is unbranched, unsubstituted C2-C10 alky]; and Het 2 is unsubstituted imidazole-! -yl or unsubstituted 1, 2, 4 triazol-2-yl.
  • the compound represented by Structural Formula (la) or (I) may exclude compounds wherein one of R 1 and R is H and the other is methyl or ethyl, for example, when: Het 1 is unsubstituted pyrid- 2-yl; X is O; Y is unbranched, unsubstituted C 2 -C 10 alkyl; and Het 2 is unsubstituted imidazole- ! - yl or unsubstituted I, 2, 4 tnazol-2-yi.
  • the compound represented by Structural Formula (la) or (I) may exclude compounds wherein X is S, for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R ⁇ are each H; Y is unbranched, unsubstituted C2-C 10 alky] ; and Het 2 is unsubstituted imidazole- 1-yl or unsubstituted ! , 2, 4 triazol-2-yl.
  • the compound represented by Structural Formula (la) or (I) may exclude compounds wherein Y is C2-C4 alkyl substituted with methyl or ethyl, unsubstituted or methyl substituted C1-C5 alkyl, or unsubstituted Ci-Ce alkyl, for example, when: Het 1 is unsubstituted pyrid-2-yl: R 1 and R 2 are each H; X is O; and Het 2 is unsubstituted imidazole- 1-yl or unsubstituted 1 , 2, 4 triazol-2-yl.
  • the compound represented by Structural Formula (la) or (I) may exclude compounds wherein Het 2 is one of: methyl or ethyl substituted imidazole- 1-yl; unsubstituted imidazoly!; methyl or ethyl substituted imidazolyl; methyl or ethyl substituted l,-2,-4-triazol-2-yl; unsubstituted 1,-2,-4-triazolyl; methyl or ethyl substituted 1,-2,- 4-triazoiyl; unsubstituted triazolyl; and methyl or ethyl substituted triazolyl; for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R are each H; X is O; and Y is unbranched, unsubstituted C2-C4 alkyl.
  • Het may be optionally substituted pyridyl, pyrazinyl, pyrimidinyl, or pyridizinyl
  • Het 5 may be optionally substituted pyridyl
  • the compound of the pharmaceutical composition may be represented by Structural Formula (II)
  • the compound of the pharmaceutical composition may be represented by Structural Formula (III).
  • Y may include at least 4 linking atoms between X and Met 2 .
  • X may be O or a bond and Y may be C-.
  • the compound may be one of Compounds la-n.
  • the compound of the pharmaceutical composition may be represented by any of Structural Formulas (Ilia), (Illb), (Hie), (Hid), (Hie), and (Illf), wherein Z, Z f , and Z may be each independently CH or N, n may be 1-14, and R J may be H, halogen, optionally halogenated Ci-C 6 alkyl, or optionally halogenated C]-C 6 alkoxy.
  • the compound of the pharmaceutical composition may be any one of Compounds la-lv.
  • the compound of the pharmaceutical composition may be any one of Compounds la-ln.
  • each ring in the optionally substituted linking moiety represented by A may be independently and optionally substituted by one or more of: hydroxy, halo, and CJ -CJO , e.g., C-.-Ce alkoxy.
  • A may include an optionally substituted heteroaryl or optionally substituted heterocycloalkyl ring.
  • A may include an optionally substituted, oxygen-containing, heteroaryl or heterocycloalkyl ring.
  • A may include an optionally substituted furanyl or optionally substituted tetrahydrofuranyl ring.
  • A may include optionally substituted 2,5 -furanyl.
  • A may include one or two optionally substituted phenyl rings.
  • A may include optionally substituted 1,4-phenyl.
  • A may be optionally substituted 1 ,4-phenyl.
  • A may be optionally substituted phenyl-heteroaryl-phenyl.
  • the compound may be represented by Structural Formula (IV), wherein each R 3 may independently represent H, halogen, optionally halogenated Ci-Ce alkyl, or optionally halogenated Ci-Cf, alkoxy.
  • the compound may be represented by Structural Formula (V).
  • the compound of the pharmaceutical composition may be represented by any of Structural Formulas (V), (Va), (Vb), (Vc), (Vd), and (Ve), wherein Z, Z 1 , and 7s may be each independently CH or N, n may be 1-14, and R J may be H, halogen, optionally halogenated Ci-Ce alkyl, or optionally halogenated Ci-Ce alkoxy.
  • the compound may be represented by Structural Formula (Via) wherein R 4 may be H, optionally halogenated C-.-Cs alkyl, or optionally halogenated aryl.
  • the compound may be represented by Structural Formula (Vlb).
  • Met 2 raay include an optionally substituted one of: pyrrole, diazole, thiadiazole, oxadiazole, and triazole.
  • Het 2 may be optionally substituted imidazole or optionally substituted 1, 2, 4 triazole.
  • the compound may be represented by Stmctural Formula (VII), wherein: Z may be CH or N; each R 3 may independently be H, halogen, optionally halogenated Cj-Ce alkyi, or optionally halogenated Cj-Ce alkoxy; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 2a-2g.
  • the compound may be, for example, one of Compounds 3a-3g.
  • the compound may be, for example, one of Compounds 4a-4m, e.g., 4a ⁇ 4i.
  • the compound may be, for example, one of Compounds 13a- 13c.
  • the compound may be represented by Stmctural Formula (VIII), wherein each R 5 may independently be H, halogen, Ci-C 4 alkyl, or C1-C4 alkoxy, and R 6 may be H, optionally halogenated Ci-Ce alky , optionally halogenated phenyl, or optionally halogenated biphenyl.
  • R 5 may independently be H, halogen, Ci-C 4 alkyl, or C1-C4 alkoxy
  • R 6 may be H, optionally halogenated Ci-Ce alky , optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be one of Compounds 5a-5f.
  • the compound may be represented by Structural Formula (IX), wherein: each R 5 may independently be H, halogen, C1-C4 alkyi, or C1-C4 alkoxy; and R 6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • R 5 may independently be H, halogen, C1-C4 alkyi, or C1-C4 alkoxy
  • R 6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be one of Compounds 6a-Sf.
  • the compound may be represented by Structural Formula (X) wherein: each R 5 may independently be H, halogen, C1-C4 alkyl, or C1-C4 alkoxy; and R 6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • R 5 may independently be H, halogen, C1-C4 alkyl, or C1-C4 alkoxy
  • R 6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be one of Compounds 7a-7f.
  • the compound may be represented by Structural Formula (XI), wherein each R 5 may independently be H, halogen, -C4 alkyl, or Cj-C 4 alkoxy; and R 6 may be H, optionally halogenated C-.-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • R 5 may independently be H, halogen, -C4 alkyl, or Cj-C 4 alkoxy
  • R 6 may be H, optionally halogenated C-.-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be represented by Stractural Formula (XII), wherein each R 5 may independently be H, halogen, C-.-C4 alkyl, or C1-C4 alkoxy; and R 6 may be H, optionally halogenated C Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be represented by Stmctural Formula (la) or (I), wherein A may be phenyl and X may be a bond.
  • the compound may be represented by Structural Formula (XIII), wherein Z may be CH or N; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 8a-8b.
  • the compound may be represented by Structural Formula (la) or (I), wherein A may be a bond.
  • the compound may be represented by Structural Formula (XIV), wherein Z may be CH or N; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 9a ⁇ 9d, for example, 9a ⁇ 9c.
  • the compound may be represented by Structural Formula (XV), wherein Z, Z 3 , and Z 2 may be each independently CH or N, n may be 1-14, and R 3 may be H, halogen, optionally halogenated Ci- e alky], or optionally halogenated Ci-Ce alkoxy.
  • the compound may be represented by one of Structural Formulas (XVa)-(XVc).
  • the compound may be one of Compounds 10a- 10 ⁇ .
  • the compound may be represented by one of Structural Formulas (XVI) and (XVII), wherein Z, Z ! , and Z 2 may be each independently CH or N, n may be 1-14, and R' may be H, halogen, optionally halogenated Ci-C alkyl, or optionally halogenated i-C alkoxy.
  • the compound may be represented by one of Structural Formulas (XVIa)-(XVIb).
  • the compound may be one of Compounds lla-lld.
  • the compound may be represented by one of Structural Formulas (XVIIa)-(XVIIb), e.g., the compound may be Compound 12a.
  • kits for anti-parasite treatment of a subject in need thereof may include any anti-parasitic compound described herein, for example, the compound represented by Structural Formula (la):
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R ! and R 2 may independently be H, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. I ' ach ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycioalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted Ci-C alkyl or optionally substituted ( " ⁇ -( j t alkenyl, e.g., optionally substituted -C1 0 alkyl or optionally substituted C 2 -C 10 alkenyl, or optionally substituted Ci-Cs alkyl or optionally substituted C 2 -C 8 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising I, 2, or 3 ring heteroatoms.
  • Het 1 may be an optionally substituted, nitrogen-containing heteroaryl.
  • 1 and R " may independently be H, optionally substituted Ci-C (s alkyl, or optionally substituted C3-C6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cy cloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C1-C 14, e.g., d ⁇ do alkyl or optionally substituted d-d 4 , e.g., d- o alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • the kit may include instructions. The instructions may direct a user to provide the subject, the subject being infected by a parasite or at risk of infection by the parasite. The instructions may direct a user to administer the compound or the pharmaceutical composition to the subject in an amount effective to mitigate infection by the parasite in the subject.
  • (la) or (I) may include any aspect of the anti-parasitic compounds described herein, either alone or as encompassed by any of the methods or pharmaceutical compositions described herein.
  • the instructions may direct a user to conduct any step or combination of steps described herein for the method.
  • AIAs and antifungal azole drugs each include a nitrogen-containing heterocycle bound to a linear or curved linker.
  • a known target of azole antifungal drugs is the CYP51 enzyme, which participates in sterol biosynthesis.
  • the crystal structure of CYP51 from L. infantum has been reported in the form of a bound fluconazole molecule interacting with the heme portion of CYP51 through coordination of a triazole nitrogen with the heme iron atom.
  • Such a structure is consistent with known crystal structures of other CYP51 -azole complexes, which also show a complex between the heme iron atom and the azole nitrogen.
  • VNI kinetoplastid CYP51
  • FIG. 1 binds with a 3 ⁇ 4 of 70 nM to T. cruzi CYP51 and inhibits the growth of intracellular T. cruzi amastigotes by 50% at a concentration of 1.3 nM.
  • VNI also treats T. cruzi infections in murine models of Chagas disease. VNI has been crystallized with T.
  • VNI/VNF a molecule similar to VNI, termed VNI/VNF (FIG. 1), is also a known inhibitor of L. infantum CYP51, although no studies against Leishmama parasites were reported.
  • the anti-parasitic compounds disclosed herein were designed by combining carefully selected AIA fragments and azole fragments. The disclosed anti -parasitic compounds were then synthesized and tested as detailed in the following Examples.
  • FIG. 2A is a synthetic scheme various phenoxyalkyl linker anti-parasitic
  • 2A included: a) ⁇ , ⁇ -dibromoalkane, K2CO 3 , acetone; b) imidazole or 1,2,4-triazole, K2CO 3 , CH 3 CN; c) SnCl 2 .2H 2 0, EtOAc; d) 5-(2-naphthylmethy])-2-pyridy thioimidate hydrobromide, CH 3 CN/EtOH (1 :3), rt.
  • FIG, 2B is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted meta to the arylimidamide group, e.g., Compounds lo-lq.
  • FIG, 2C is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted ortho to the arylimidamide group, e.g., Compounds lr-lt.
  • reagents and conditions for synthesis of compounds according to FIG, 2C included: a) RI, K 2 C0 3 , sealed tube, 80°C; b) NaOH, DMSO, reflux; c) 1,8-Dibromooctane, K 2 C0 3 , CH 3 CN, reflux; d) imidazole, K 2 C0 3 , CH 3 CN, reflux; e) 8 ⁇ 2 ' 2 ⁇ 2 0, EtOAc, ref!ux; f) S ⁇ (2 ⁇ naphih ⁇ 'lmethyl)thioimidaie hydrobromide, CH 3 CN/EtOH, rt..
  • FIG, 2D is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted with pyrrole, e.g., Compound In.
  • reagents and conditions for synthesis of Compound lu according to FIG. 2D included: a) 1,8-dibromooctane, K 2 C0 3 , acetone; b) pyrrole, K 2 C0 3 , CH 3 CN; c) SnCl 2 .2H 2 0, EtOAc; d) _?-(2-naph lmethyl)-2- pyridylthioimidate hydrobromide, CH 3 CN/EtOH (1 :3), rt.
  • FIG. 3A is a synthetic scheme for various phenyl-unsubstituted diphenylfuran alkyloxy linker hybrid Compounds 2a ⁇ 2g and 3a-g. Compounds 2a-e, 2g, 3a-e, and 3g were made according to FIG. 3A. Compound 2h was made according to FIG. 3A, but starting with 1- bromo-2-oxy(prop-2-yl)-4-nitrobenzene. Generally, reagents and conditions for synthesis of compounds according to FIG.
  • 3A included: a) Pd(PPh ) 4 , dioxane, 90°C; b) NBS, DMF, rt; c) K 2 C0 3 , acetone, reflux; d) Pd(PPh 3 ) 4 , K 2 C0 3 , MeOH, toluene, 80°C; e) azole, NaH, DMF, rt; ! ' ) H 2 , Pd(C), EtOH-EtOAc; g) (i) 5-(2-naphthylmethyl-2-pyridylthioimidate hydrobromide, EtOH; (ii) NaOH; (iii) ethanolic HC1.
  • Tetrakistriphenylphosphine palladium (0.5 mmol) was added to a stirred mixture of the 2-(tributylstannyl) furan (11 mmol) and 1 -bromo-4-nitrobenzene (10 mmol) in deaerated dioxane (25 mL) under a nitrogen atmosphere. The vigorously stirred mixture was heated at 90- 100 °C for 24 h. The solvent was evaporated under reduced pressure, the resulting solid was partitioned between ethyl acetate (200 mL) and 5 mL of concentrated ammonia to remove the palladium complex, washed with water, passed through celite to remove the catalyst, dried over sodium sulfate and evaporated.
  • N-bromosuccinimide (2.13 gm, 12 mmol) was added portion-wise to a stirred solution of the previous nitro compound (10 mmol) in dimethylformamide (20 mL). The reaction mixture was stirred at room temperature for 12 h then poured onto cold water, the precipitate was collected and dried. Purification was conducted by column chromatography on silica gel, using hexanes/ethyl acetate (95/5, v/v). Yellow solid, yield 96 %; nip.
  • 1,4-dibromobutane (36 mmol) was added to a solution of the p- hydroxyphenylboronic acid ester (1.32 gm, 6 mmol), dry K2CO 3 (1.65 gm, 12 mmol) and CS2CO 3 (0.39 gm, 1.2 mmol) in anhydrous dimethylacetamide (15 mL) under a nitrogen atmosphere. Stirring was continued for 12 h and ice water was added and the reaction mixture was filtered and air dried. Purification was performed by column chromatography on silica gel, using hexanes/ethyl acetate (93/7, v/v). White solid (73%) rn.p.
  • the precipitate was filtered and washed with dry ether.
  • the solid was dissolved in ethanol (2 mL); the solution was cooled to 0 °C in an ice bath and 1 0% NaOH was added until pH reached approximately 10.
  • the free base was extracted with ethyl acetate (3 50 mL). The organic layer was washed with distilled water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting suspension was crystallized by adding dry hexanes and then filtered.
  • the free base was suspended in dry ethanol (20 mL) and cooled to 0 °C in an ice bath. Freshly prepared ethanolic HCl solution (2 mL) was added to the suspension and the mixture was stirred at room temperature for overnight.
  • FIG. 3B is a synthetic scheme for various phenyl substituted diphenylfuran alkyioxv linker hybrid compounds, each of which may be prepared, for example, from a suitably substituted aryl boronate according to FIG. 3A.
  • compounds may be prepared from the corresponding phenol and bromoalkyi imidazole, as shown in FIG. 3B.
  • the phenol may be prepared from a phenol protected aryl boronate according to FIG. 3A, followed by subsequent deprotection.
  • Compound 4j was made according to FIG. 33B.
  • reagents and conditions for synthesis of compounds according to FIG. 3B included: a) Pd(PPh 3 )4, dioxane, 90°C; b) NBS, DMF, rt; c) K 2 C0 3 , Cs 2 C0 3 , DMA, rt; d) Pd(PPh 3 ) 4 , K 2 C0 3 , MeOH, toluene, 80°C; e) imidazole, NaH, DMF, rt; f) H 2 , Pd(C), EtOH-EtOAc; g) (1) ,S'-(2-naphthylmethyl)-2- pyndylthioimidate hydrobromide, EtOH; (ii) NaOH.
  • FIG. 3C is a synthetic scheme for various phenyl substituted diphenylfuran alkyloxy linker hybrid compounds.
  • Compounds 2h, 4k, 13b, and 13c were made according to FIG. 3C.
  • reagents and conditions for synthesis of compounds according to FIG. 3C included: aa) Pd(PPh 3 ) 4 , dioxane, 90°C; b) NBS, DMF, rt; c) K 2 C0 3 , Cs 2 C0 3 , DMA, rt; d) Pd(PPh 3 ) 4 , K CO :.
  • FIG. 3D is a prophetic synthetic scheme for various diphenylfuran alkyloxy linker hybrid Compounds 4a-i, each of which may be prepared, for example, from a suitably substituted aryl boronate according to FIG. 3A.
  • Compounds 4a-i may be prepared from the corresponding phenol and bromoalkyi imidazole, as shown in FIG. 3D.
  • the phenol may be prepared from a phenol protected aryl boronate according to FIG. 3A, followed by subsequent deprotection.
  • Example 4 Synthesis of Alkylamide Linker Anti-Parasitic Compounds
  • FIG, 4 is a synthetic scheme for various alkylamide linker hybrid Compounds
  • precursor carboxylic acids were prepared similarly to FIG. 3A by a cross-coupling of a benzylaicohoi boronate ester with 2-(4-nitrophenyl)furan, nitro reduction, and imidamide formation.
  • Oxidation of the benzyl alcohol provided the carboxylic acid compound shown in FIG. 4, and subsequent peptide coupling with the illustrated imidazoyl amine is proposed to afford Compounds 5a and 5c.
  • Compound 6a may be prepared from 2-(4- nitrophenyl)furan, followed by nitro reduction and imidamide formation. Bromination of the resulting furanyi compound followed by a metal -mediated carboxylation may provide the carboxylic acid shown in FIG. 4. Subsequent peptide coupling with the illustrated imidazoyl amine may afford Compound 6a.
  • Compound 7a may be prepared from a suitable 4-aminobenzoic acid derivative. Imidamide formation may provide the carboxylic acid compound shown in FIG. 4, and subsequent peptide coupling with the illustrated imidazoyl amine may provide Compound 6a.
  • FIG. 5A is a prophetic synthetic scheme for various phenylalkyl linker hybrid
  • Compounds 8a and 8b may be prepared from phenyllithium and the corresponding dibromoalkane, as shown in FIG. 5A. Nitration of the resulting aikylaryl bromide followed by displacement of the bromide with imidazole can provide the nitrophenyl alkylimidazole. Subsequent reduction of the nitro group to the amine, followed by ami dine synthesis with naph1halene-2-ylmethylpyridine-2-carbimidothioate may provide Compounds 8a and 8b.
  • FIG. SB is a synthetic scheme for various phenylalkyl linker hybrid
  • the product was obtained after column chromatography purification over neutralized silica gel with DCM/MeOH (100: 1 ) as a brown oil of the protected aminoalkyl imidazole, 0.48 g.
  • a dry 25 mL two-necked flask was charged with Pd/C (10%, 0.15 g) and the protected amine (0.48 g, 1.45 mmol) in 20 mL absolute ethanoi under nitrogen. The mixture was stirred under 1 atmosphere of hydrogen for 24 hours.
  • the precipitate was filtered and washed with dry ether.
  • the solid was dissolved in ethanol (2 mL); the solution was cooled to 0 °C in an ice bath and 10% NaOH was added until the pH reached approximately 10.
  • the free base was extracted with ethyl acetate (3 ⁇ 25 mL).
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the resulting suspension was purified by column chromatography over silica gel using DCM/MeOH/TEA (9.5: 1.2:0.6) as eluent then further purified by 5 mL hexanes/di ethyl ether (1 : 1) to yield a buff powder, 0,085 g, 55%.
  • FIG. 6A is a synthetic scheme for various unsubstituted and substituted biphenyl linker anti-parasitic compounds, which was used to produce Compounds 19a, lOd, 19e, lOh, 10k, and 101. Biphenyl linkers in these compounds were either unsubstituted or were substituted meia to the amidine group. Generally, reagents and conditions for synthesis of compounds according to FIG.
  • 6A included: dibromoaikane, K2CO 3 , CH 3 CN, reflux; b) imidazole, K 2 C0 3 , CH3CN, reflux; c) 2-aikoxy-4-nitroiodobenzene, Pd(dppf)Cl 2 , K2CO3, DMSO, 100°C; d) SnCl 2 .2H 2 0, EtOAc, reflux; e) 5-(2-naphthylm.ethyl)-2-pyndylthioimidate hydrobromide, CH 3 CN/EtOH (1 :3), rt.
  • FIG. 63B is a synthetic scheme for various substituted biphenyl linker antiparasitic compounds, which was used to produce Compounds 10b, 10c, lOi, and lOj. Biphenyl linkers in these compounds were substituted or (ho to the amidine group. Generally, reagents and conditions for synthesis of compounds according to FIG.
  • 6B included: a) dibromoalkane, K2CO3, CH3CN, reflux; b) imidazole, 2 C0 3 , CH 3 CN, reflux; c) 23a,b, Pd
  • FIG. 6C is a synthetic scheme for various substituted biphenyl linker antiparasitic compounds, which was used to produce Compounds lOf and 10m. Biphenyl linkers in these compounds were substituted meta to the aikoxy linking group. Generally, reagents and conditions for synthesis of compounds according to FIG.
  • 6C included: a) TsCl, K 2 C0 3 , acetone, reflux; b) Mel, K 2 C0 3 , sealed tube, CH 3 CN, reflux; c) bis(pinocolato)diboron, Pd(dppf)Cl 2 , AcOK; d) 4-nitro-iodobenzene, Pd(dppf)Cl 2 , dimethoxyethane/DMF/water (7:3: 1), reflux; e) aq NaOH, EtOH/DMSO; f) 1,4-dibromo butane or 1,6-dibromohexane, K 2 C0 3 , CH 3 CN, reflux; g) imidazole, K2CO3, CH3CN, reflux; h) SnCl2.2H 2 0, EtOAc, reflux; i) 5-(2-naphthy1methyl)-2- pyridylthioimidate hydrobromide, CH 3 CN/Et
  • FIG. 6D is a synthetic scheme for various substituted biphenyl linker antiparasitic compounds, which was used to produce Compounds lOg and 10 ⁇ . Biphenyl linkers in these compounds were substituted ortho to the aikoxy linking group. Generally, reagents and conditions for synthesis of compounds according to FIG.
  • 6D included: a) TsCl, acetonitrile, 2CO 3 , reflux ; b) Bis(pinacolato)diboron, Pd(dppf)Cl 2 , AcOK, dioxane, 100°C; c) l-Iodo-4- nitrobenzene, Pd[P(Ph) 3 ] 4 or Pd(dppf)Cl 2 , K 2 C0 3 , DME:DMF:H 2 0 (7:3: 1 ),100°C; d) aq NaOH, EtOH/DMSO; e) dibromoalkane, acetonitrile, K 2 C0 3 , reflux; f) Imidazole, K CO ;, reflux; g) SnCl 2 .2H 2 0, ethyl acetate, reflux; h) 5 , -(2-naphthylmethyl)-2-pyridylthioimidate hydrobromide
  • FIG. 7A is a synthetic scheme for various phenyl-piperazinyl-phenyl linker anti-parasitic compounds, which was used to produce Compounds lla-lld. Generally, reagents and conditions for synthesis of compounds according to FIG.
  • 7A included: a) NMP, DIPEA, 4- chloronitrobenzene; b) ⁇ , ⁇ -dihaloalkane, K 2 C0 , acetone or Cs 2 C0 , DMF; c) imidazole or 1 ,2,4-triazole, Cs 2 C0 3 , DMF; d) Pd/C, H 2 , EtOAc/MeOH; e) ,S-(2-naphthylmethyI-2- pyridylthioimidate hydrobromide, CH 3 CN/EtOH.
  • FIG. 7B is a synthetic scheme for various phenyi-piperazinyl linker antiparasitic compounds, e.g., corresponding to Structural Formula (XVII). Generally, reagents and conditions for synthesis of compounds according to FIG.
  • 7B included: a) K 2 C0 3 /DMSO; b) ⁇ , ⁇ -dihaloalkane, e.g., 1,6-dibromohexane, Cs 2 C0 3 , DMF; c) imidazole, Cs 2 C0 3 , DMF; d) Pd/C, H 2 , MeOH; e) 5-(2-naph1hylmethyl-2-pyridylthioimidate hvdrobromide, CH ⁇ CN/EiOH.
  • ⁇ , ⁇ -dihaloalkane e.g., 1,6-dibromohexane
  • imidazole Cs 2 C0 3 , DMF
  • Pd/C H 2 , MeOH
  • Step 2 Synthesis of l-(6-bromohexyl)-4-(4-nitrophenyl)piperazine
  • Step 3 Synthesis of I-(6-( lH-imid zol-i-yl)hex >l) ⁇ 4 ⁇ (4 ⁇ nitrophenyl)piperazi
  • Step 5 Synthesis of -(4-(4-(6-(lH4midazol-l-yl)hexyl)piperazin-l-yl)phenyl) picolinimidamide
  • HBSS Hank's Balanced Salt Solution
  • compounds or the standard drag amphotericin B were added in two-fold serial dilutions in macrophage medium at a final volume of 200 ⁇ iL/well. Plates were then incubated for three days under the conditions described previously. After incubation, medium was removed and cells were washed with HBSS. Fixation of the cells was then performed using 10% formalin for 30 rain. Cells were then permeabilized with 0.1% Triton in PBS, washed with PBS, and stained with 1
  • HBSS Hank's Balanced Salt Solution
  • J774 macrophages were maintained in R MI + GlutaMAX medium (Gibco) supplemented with 100 U/mL penicillin, 100 ⁇ / ⁇ , streptomycin, and 10% fetal bovine serum at 37°C in a humidified 5% CO? atmosphere. Macrophages were plated at a density of 5 ⁇ 10 3 cells/well in the presence or absence of serial dilutions of test compounds, vehicle, or podophyllotoxin standard drug in a final volume of 100 uL.
  • HepG2 cells (5 10 ⁇ ' in 100 ⁇ ) were incubated for 72 h with serial dilutions of compounds in DMEM medium supplemented with 1 0% fetal bovine serum and antibiotics. MTT was added and absorbance at 570 nm provided an assessment of cell proliferation versus compound concentration, from which CCso against HepG2 was determined in ⁇ . See Werbovetz, K., et al. Int. J. Toxicol 2014, 33, 282-287, the entirety of which is incorporated herein by reference.
  • Example 8A Biological Evaluation of Phenoxyalkyl Linker Compounds Against L. Donovani, CC5 0 values against J774 macrophages, and CC5 0 values against HepG2
  • FIG. 8A is a table demonstrating IC5 0 values in ⁇ against intracellular L. donovani, CC50 values against J774 macrophages, and CC50 values against HepG2 for various phenoxyalkyl linker compounds compared to amphotericin B, podophyllotoxm, and doxorubicin.
  • Example 8B Biological Evaluation of Diphenylfuran Alkyloxy Linker Compounds
  • FIG. 8B is a table demonstrating IC5 0 values in ⁇ against intracellular L. donovani, and CC5 0 values against J774 macrophages, and HepG2 for various diphenylfuran linker compounds compared to amphotericin B, podophyllotoxm, and doxorubicin.
  • Example 8C Biological Evaluation of Biphenyl Alkyloxy Linker Compounds Against L. Donovani, CC5 0 values against J774 macrophages, and CC5 0 values against HepG2
  • FIG. 8C is a table demonstrating IC5 0 values in ⁇ against intracellular L. donovani, CC50 values against J774 macrophages, and CC50 values against HepG2 for various biphenyl linker compounds compared to amphotericin B, podophyllotoxm, and doxorubicin.
  • Example 8F Biological Evaluation of Phenyl-Piperazinyl-Phenyl Alkyloxy Linker Compounds against L. donovani, and CC5 0 values against J774 macrophages
  • FIG. 8D is a table demonstrating IC5 0 values in ⁇ against intracellular L. donovani and CC50 values against J774 macrophages for various phenyl-piperazinyl-phenyl linker compounds compared to amphotericin B and podophyllotoxm.
  • an "alkyl” group includes straight chain and branched chain alkyl groups having a number of carbon atoms, for example, from 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4.
  • straight chain alkyl groups include groups such as methyl, ethyl, n- propyl, ⁇ -butyl, n-pentyl, n-hexyl, ⁇ -heptyl, and n-octyl groups.
  • branched alkyl groups include, e.g., isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups.
  • Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above and include, without limitation, haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alk laminoalkyl, dialkyiaminoalkyl, alkoxyalkyl, or carboxyalkyl.
  • an "alkoxy” group means a hydroxy 1 group (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group.
  • linear alkoxy groups include, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy.
  • branched alkoxy groups include, e.g., isopropoxy, seobutoxy, tert-butoxy, isopentoxy, or isohexoxy.
  • cycloalkoxy groups include, e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.
  • Representative substituted alkoxy groups may be substituted one or more times.
  • a '"cycloaikyi” group includes mono-, hi- or tricyclic alkyl groups having from 3 to 12 carbon atoms in each ring, for example, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms.
  • Exemplar ⁇ ' monocyclic cycloaikyi groups include, for example, cvclopropvl, cyclobutyl, cyclopentyl, cyciohexyi, cycloheptyl, cyclooctyl, and the like.
  • a cycloaikyi group may have a number of ring carbons of from 3 to 8, 3 to 7, 3 to 6, or 3 to 5.
  • Bi- and tricyclic ring systems may include both bridged cycloaikyi groups and fused rings, e.g., bicyclo[2.1.1]hexane, adamantyl, decaiinyl, and the like.
  • Substituted cycloaikyi groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above.
  • Substituted cycloaikyi groups may include rings that may be substituted with straight or branched chain alkyl groups.
  • Representative substituted cycloaikyi groups may be mono-substituted or substituted more than once, for example, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyciohexyi groups.
  • a heterocycloalkyl means an aromatic carbocyclic ring having one or more ring carbon atoms replaced by a heteroatom (e.g., N, S, or O).
  • Non-aromatic heterocy devis rings may have 4, 5, 6, 7, or 8 ring atoms. Examples include oxazolinyl, thiazolinyl, oxazolidinyl, thiazoiidinyl, tetrahydrofuranyl, tetrahyrothiophenyl, morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl, thiazoiidinyl, and the like.
  • an " 'aryF” group means a carbocyclic aromatic hydrocarbon.
  • Aryi groups herein include monocyclic, bi cyclic and tricyclic ring systems.
  • Aryi groups include, e.g., phenyl, azulenyl, heptalenyl, biphenyl, ffuorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, naphthyl, and the like, for example, phenyl, biphenyl, and naphthyl.
  • Aryi groups may contain, for example, 6 to 14, 6 to 12, or 6 to 10 ring carbons.
  • the aryi groups may be phenyl or naphthyl.
  • aryi groups may include groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl or tetrahydronaphthyl), an "aryi" group, unless stated to be substituted or optionally substituted, does not include aryi groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl may be referred to as substituted aryi groups.
  • Representative substituted aryi groups may be mono-substituted or substituted more than once.
  • monosubstituted aryi groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl, which may be substituted with substituents such as those above.
  • an "aralkyl” group means an alkyl group in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryi group.
  • aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms.
  • Substituted aralkyl groups may be substituted at the alkyl, the aryi or both the alkyl and aryl portions of the group.
  • Representative aralkyl groups include, e.g., benzyl and phenethyi groups and fused (cycloalkylaryl)alkyl groups such as 4-indanylethyl.
  • Substituted araikyis may be substituted one or more times.
  • a "heteroaryl” group means a carbocyclic aromatic ring having one or more ring carbon atoms replaced by a heteroatom (e.g., N, S, or O).
  • Heteroaryl groups may include, for example, imidazolyl, isoimidazolyi, thienyi, furanyi, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrrolyl, pyrazmyl, thiazoyl, isothiazolyl, oxazolyl, isooxazoiyl, 1,2,3- trizaolyl, 1 ,2,4-triazolyl, and tetrazoiyl.
  • Heteroaryl groups also include fused poly cyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings.
  • heteroaryl groups may include benzothienyi, benzofuranyl, indolyl, qumolinyl, benzothiazolyl, benzoisothiazolyi, benzooxazolyl, benzoisooxazolyl, benzimidazolyi, quinolinyl, isoquinolinyl and isoindolyl.
  • Groups described herein having two or more points of attachment may be designated by use of the suffix, "ene.”
  • divalent alkyl groups may be alkylene groups
  • divalent aryl groups may be arylene groups
  • divalent heteroaryl groups may be heteroarylene groups, and so forth.
  • certain polymers may be described by use of the suffix "ene " ' in conjunction with a term describing the polymer repeat unit.
  • substituted means a compound or group that may be substituted or unsubstituted.
  • substituted refers to an organic group (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein may be replaced by a bond to non-hydrogen or non-carbon atoms.
  • Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom may be replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • a substituted group may be substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group may be substituted with 1 , 2, 3, 4, 5, or 6 substituents.
  • substituent groups include: halogens (F, CI, Br, and I); hydroxy!: alkoxy, alkenoxy, aryioxy, aralkyloxy, heterocyclooxy, and heterocycloalkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxy amines; aralkoxy amines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; or nitnles.
  • halogens F, CI, Br
  • a "per"- substi luted compound or group is a compound or group having all or substantially all substitutable positions substituted with the indicated substituent.
  • 1,6-diiodo peril uoro hexane indicates a compound of formula C 6 F 12 I 2 , where all the substitutable hydrogens have been replaced with fluorine atoms.
  • suitable substituents for an aikyl group, cycioalkyl group, heterocycioalkyl group, or an aryl group ring carbon are those which do not substantially interfere with the activity of the disclosed compounds. Examples include -OH, halogen (-Br, -, - I and -F )- -OR ⁇ -0(CO)R A , -(CQ)R A , -CN, -N0 2 , -CO ? H, -S0 3 H, -N33 ⁇ 4, -NHR A , -N(R A R B ), - (C())OR A , - ⁇ CO )! !.
  • Each of R A -R may independently be an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group, for example, an alkyi, benzylic or aryl group.
  • -NR A R D taken together, may form a substituted or unsubstituted non-aromatic heterocyclic group.
  • a non-aromatic heterocyclic group, benzylic group or aryl group may al so have an aliphatic or substituted aliphatic group as a substituent.
  • a substituted aliphatic group may also have a non-aromatic heterocyclic ring, a substituted a non- aromatic heterocyclic ring, benzyl, substituted benzyl, aryl or substituted aryl group as a substituent.
  • a substituted aliphatic, non-aromatic heterocyclic group, substituted aryl, or substituted benzyl group may have more than one substituent.
  • Suitable substituents for heteroaryl ring nitrogen atoms having three covalent bonds to other heteroaryl ring atoms may include -OH and Ci to C 10 alkoxy .
  • Substituted heteroaryl ring nitrogen atoms that have three covalent bonds to other heteroaryl ring atoms are positively charged, which may be balanced by counteranions such as chloride, bromide, formate, acetate and the like. Examples of other suitable counteranions may include counteranions found in the described pharmacologically acceptable salts.
  • Suitable substituents for heteroaryl ring nitrogen atoms having two covalent bonds to other heteroaryl ring atoms include alkyl, substituted alkyl (including haloaikyi), phenyl, substituted phenyl, -S(0) 2 -(aikyl), -S(0) 2 -NH(alkyl), -S(()) 2 -NH(alkyl) 2 , and the like.
  • compositions described herein may react with any of a number of organic or inorganic acids to form a salt.
  • compounds disclosed herein that possess a sufficiently acidic functional group may react with any of a number of organic or inorganic bases to form a salt.
  • Acids commonly employed to form acid addition salts from compounds with basic groups may include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p- bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p- bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts may include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, huiyne-l,4-dioate, hexyne-l ,6-dioate, benzoate, chlorobenzoate, methyibenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenyiacetate, phenylpropionate
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of the described compounds may include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like.
  • An “effective amount” is the quantity of compound in which a beneficial clinical outcome may be achieved when the compound is administered to a subject suffering from the described parasite.
  • a “beneficial clinical outcome” may include one or more of: a reduction in number of parasites in a subject; a reduction in the rate of parasite growth in a subject; a reduction in parasite consumption of a subject's bodily resources; a reduction in biomarkers, toxins, proteins, peptides, and other biomolecules associated with infection of the subject by the parasite; a reduction in inflammatory, allergic, toxic, disfigurement, or other effects on the subject by the parasite; a reduction in the severity of the symptoms associated with the parasite and/or an increase in the longevity or health of the subject compared with the absence of the treatment.
  • the precise amount of compound administered to a subject may depend on the species, iifecycie, of the parasitical infection.
  • the precise amount of compound administered to a subject may also depend on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. A skilled artisan may determine appropriate dosages depending on these and other factors. Effective amounts of the disclosed compounds typically range between about 1 mg/mnr per day and about 10 grams/mm per day, and preferably between 10 mg/mni per day and about 5 grams/mm 2 .
  • the disclosed compounds and pharmaceutical compositions may be administered by any suitable route, including, for example, orally in tablets, pills, gelcaps, lozenges, or suspensions; by parenteral administration.
  • Parenteral administration can include, for example, systemic administration, such as by intramuscular, intravenous, subcutaneous, or intraperitoneal injection.
  • the compounds may also be administered, for example, orally (e.g. , dietary); topically, in the form of creams, sprays, patches, and the like; by inhalation (e.g.
  • oral or parenteral administration are exemplary modes of administration.
  • the disclosed compounds may be administered to the subject in conjunction with an acceptable pharmaceutical earner as part of a pharmaceutical composition for treatment of infection by the described parasite.
  • Formulation of the compound to be administered may vary according to the route and vehicle of administration selected (e.g., solution for injection, capsule or tablet for ingestion, and the like).
  • Suitable pharmaceutical carriers may contain inert ingredients that do not interact with the described compound. Standard pharmaceutical formulation techniques may ⁇ be employed, such as those described in Remington's Pharmaceutical Sciences, 22 nd ed., Mack Publishing Company, Easton, PA, 2012.
  • Suitable pharmaceutical earners for parenteral administration may include, for example, sterile water, physiological saline, bacteriostatic saline (e.g., saline containing about 0.9% mg/mL benzyl alcohol, and the like), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like.
  • a "subject" may be any animal subject to infection by the described parasites, e.g., the subject may be a mammal, bird, marsupial, fish, or amphibian.
  • the subject may be a mammal, such as a human.
  • the subject may also be a domestic or wild animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like), laboratory animals (e.g., rats, mice, guinea pigs, and the like), birds, fish, marsupials, and the like.
  • the term “about” in conj unction with a number is intended to include ⁇ 1 0% of the number. In other words, “about 10” may mean from 9 to 11. Where the term “about” is used with respect to a number that is an integer, the term “about” may mean ⁇ 10% of the number, or ⁇ 5, ⁇ 4, ⁇ 3, ⁇ 2, or ⁇ 1 of the number.

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Abstract

Provided are compounds, methods, and pharmaceutical compositions useful for treatment of parasites, e.g., Leishmania. For example, the compound may he represented by Ar—C(=NR1)NR2—A—X—Y—Het2, and pharmaceutically acceptable salts thereof. Ar may be an optionally substituted, aryl or nitrogen-containing heteroaryl. R1 and R2 may independently represent H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted C1-C14 alkyl or optionally substituted C2-C14 alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.

Description

ANTI-PARASITIC COMPOUNDS
CROSS-REFERENCE TO RELATED APPLIC ATIONS
[0001] lliis application claims priority from U.S. Provisional Patent Application No. :
62/381 ,087 filed on August 30, 2016, the entire contents of which are incorporated herein by reference.
BACKGROUND
10002] Leishmaniasis is a spectrum of disease that ranges from cutaneous lesions to life- threatening visceral infections caused by sandf!y-carried pathogenic Leishmania species, of which at least twenty are known. The number of cases of visceral leishmaniasis (VL) was recently estimated as 200,000 to 400,000 per year, with about three times as many cases of cutaneous leishmaniasis (CL). VL may include enlargement of the spleen and liver, anemia, and weight loss, and is usually fatal without effective drug treatment. A vast majority of CL cases occur in Brazil and Peru along with several countries of the Middle East, including Afghanistan, Iran, Iraq, and Syria. In CL, the sandfly bite typically progresses from a papule to a nodule to an ulcerative lesion. Such lesions may self-cure over a period of 2-15 months but may result in a persistent and potentially disfiguring scar. Other manifestations may occur, including diffuse CL (disseminated nodules), leishmaniasis recidivans (recurring infection near a healed lesion), and mucosal leishmaniasis (disfiguring lesions in the mucous membranes of the nose and mouth).
[0003 J Despite progress, there are still significant unmet needs in leishmaniasis therapy.
Antimonial drugs display serious side effects and high failure rates have prompted their removal as first line treatments against VL on the Indian subcontinent. Liposomal AmB is relatively expensive, limiting its widespread use in developing countries, and is also less effective against Brazilian and East African strains compared to India strains. Paromomycin is inexpensive and effective against Indian VL but is less useful against East African VL. Miltefosine is orally available and useful against Indian VL, but is teratogenic in lab animals. A high relapse rate was recently reported for treating VL with miltefosine in Nepal. Injectable antimonials form the basis of most treatment regimens for VL in the New World and are also typically used in the therapy of cutaneous leishmaniasis (CL), either by parenteral or intralesional injection. Miltefosine is recommended for treating CL infections caused by only L. guyanensis, L. panamensis, and L. mexicana, while parenteral pentamidine is a drug of choice for CL caused by L. guyanensis. Topical paromomycin is less costly and displays fewer side effects than antimonials but is inferior to these drugs against CL in both the Old World and the New World. The azole antifungal drugs ketoconazole, fluconazole, and itraconazole have all been evaluated in clinical trials against leishmaniasis. While these azoles are orally available and have shown clinical activity against VL and CL, they lack consistent efficacy. Arylimidamides (AT As) possess in vitro anti-leishmanial activity and in vivo efficacy in rodent VL models, but higher activity and efficacy is desirable. Studies have shown efficacy for combined application of the AIA DB766 and the azole antifungal posaconazole in vitro. Some anti-leishmanial combinations have been explored in clinical trials, and miltefosine and AmB may be synergistic in mice when given together. However, miltefosine has significant weaknesses, and no oral anti-leishmanial drug combinations exist.
[0004] The present application appreciates that developing treatments for parasite infections such as leishmaniasis may be a challenging endeavor.
SUMMARY
[0005 J In one embodiment, a compound is provided, represented by Structural Formula
(la):
(la) Ar— C (=NR! )NR2— A— X— Y— Het2
and pharmaceutically acceptable salts thereof. Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl. R1 and R may independently be H, optionally substituted Ci-C , alkyl, or optionally substituted C Ce cycloalkyl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloaikyi, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted Ci-Cu alkyl or optionally substituted C2-C 14 alkenyl, e.g., optionally substituted C-.-Cio alkyl or optionally substituted C Cjo alkenyl, or optionally substituted Ci-Cg alkyl or optionally substituted C2-Cs alkenyl. Het2 may be an optionally substituted five-membered nitrogen -containing heteroaromatic ring comprising ! , 2, or 3 ring heteroatoms. The compound represented by Structural Formula (la) may exclude free- base Compounds la-f:
Figure imgf000004_0001
Figure imgf000005_0001
[0006] In another embodiment, a compound is provided, represented by Structural
Formula (I):
(I) Het1— C(=NR1)NR2— A— — Y— Het2 and pharmaceutically acceptable salts thereof. Het1 may be an optionally substituted, nitrogen- containing heteroaryl. R! and R may independently be H, optionally substituted Cr-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heteiOcydoaikyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted Ci-Cio alkyl or optionally substituted C2-Cio alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms. The compound represented by Structural Formula (I) may exclude free-base Compounds la-f:
Figure imgf000005_0002
, and If
[0007 J In one embodiment, a method of anti -parasitic treatment in a subject in need thereof is provided. The method may include providing the subject, the subject being infected by a parasite or at risk of infection by the parasite. The method may include administering a compound to the subject in an amount effective to mitigate infection by the parasite in the subject. The compound may be represented by Structural Formula (la):
(la) Ar— C(=NRl)NR2— A— — Y- and pharmaceutically acceptable salts thereof. Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl. R1 and R2 may independently be H, optionally substituted Ci-Ce alkyi, or optionally substituted t C , cycloalkvl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkvl, heterocvcloalkyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted Cj-C-, 4 alkyi or optionally substituted C?-C j4 alkenyl, e.g., optionally substituted C-.-Cio alkyi or optionally substituted C2-Cio alkenyl, or optionally substituted Ci-Cg alkyi or optionally substituted C2-C8 alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 nng heteroatoms.
[0008] In another embodiment, a method of anti-parasitic treatment in a subject in need thereof is provided. The method may include providing the subject, the subject being infected by a parasite or at risk of infection by the parasite. The method may include administering a compound to the subject in an amount effective to mitigate infection by the parasite in the subject. The compound may be represented by Structural Formula (I):
(I) Het1— C(=NR1)NR2— A— X— Y— Het2
and pharmaceutically acceptable salts thereof. Het1 may be an optionally substituted, nitrogen- containing heteroaryl. R1 and R may independently be H, optionally substituted Ci-Ce alkyi, or optionally substituted C3-C6 cycloalkvl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycioaikyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted Ci-C io alkyi or optionally substituted C2-C10 alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
[00091 In one embodiment, a pharmaceutical composition is provided. The pharmaceutical composition may include a pharmaceutically acceptable excipient and a compound represented by Structural Formula (la):
(la) Ar— C(=NR1)NR2— A— X— Y— Het2
and pharmaceutically acceptable salts thereof. Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl. R1 and Rz may independently be H, optionally substituted Ci-Ce alkyi, or optionally substituted t C , cycloalkvl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocvcloalkyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted Cj -C-, 4 alkyi or optionally substituted C?-C j4 alkenyl, e.g., optionally substituted C i -Cio alkyl or optionally substituted C2-Clo alkenyl, or optionally substituted Ci-Cg alkyl or optionally substituted C2-Cg alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1 , 2, or 3 ring heteroatoms.
[0010] In another embodiment, a pharmaceutical composition is provided. The pharmaceutical composition may include a pharmaceutically acceptable excipient and a compound represented by Structural Formula Structural Formula (I):
(I) Het1— C(=NR1)NR2— A— X— Y— Het2
and pharmaceutically acceptable salts thereof. Het1 may be an optionally substituted, nitrogen- containing heteroaryl. R! and R may independently be H, optionally substituted Ci-C , alkyl, or optionally substituted C3-C6 cvcloalkvl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroar}'!. X may be O, S, amide, or a bond. Y may be optionally substituted Ci-C-.o alkyl or optionally substituted C2-C10 alkenyl. Het2 may be an optionally substituted five-membered nitrogen -containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
[0011] In one embodiment, a kit for anti-parasite treatment of a subject in need thereof is provided. The kit may include a compound represented by Structural Formula (I):
(la) Ar— C(=N 1)NR2— A— X— Y— Het2
[0012] and pharmaceutically acceptable salts thereof. Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl. Rf and R2 may independently be H, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl. X may be (), S, amide, or a bond. Y may be optionally substituted C1-C 14 alkyl or optionally substituted C2-C14 alkenyl, e.g., optionally substituted C1-C10 alkyl or optionally substituted C Cjo alkenyl, or optionally substituted Ci-Cs alkyl or optionally substituted CVCg alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1 , 2, or 3 ring heteroatoms.
[0013] In another embodiment, a kit for anti -parasite treatment of a subject in need thereof is provided. The kit may include a compound represented by Structural Formula (1):
(I) Het1— C(=NR1)NR2— A— — Y— Het2 and pharmaceutically acceptable salts thereof, and mixtures thereof with a pharmaceutically acceptable carrier or excipient. Het1 may be an optionally substituted, nitrogen-containing heieroaiyl R1 and R2 may independently be H, optionally substituted Ci-Cf, alky], or optionally substituted C3-C6 cycloalkyl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted C1-C10 alkyl or optionally substituted C Cio alkenyi. Met2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms. The kit may include instructions. The instructions may direct a user to provide the subject, the subject being infected by a parasite or at risk of infection by the parasite. The instructions may direct a user to administer the compound or the pharmaceutical composition to the subject in an amount effective to mitigate infection by the parasite in the subject.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The accompanying figures, which are incorporated in and constitute a part of the specification, illustrate example methods and compositions, and are used merely to illustrate example embodiments.
[0015] FIG. 1 (PRIOR ART) depicts structures of various known compounds.
[0016] FIG. 2A is a synthetic scheme for various phenoxyalkyl linker anti-parasitic compounds.
[0017] FIG. 2B is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted meta to the arylimidamide group.
[0018] FIG. 2C is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted orlho to the arylimidamide group.
[0019] FIG. 21) is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted with pyrrole.
[0020] FIG. 3A is a synthetic scheme for various phenyl-unsubstituted diphenylfuran alkyloxy linker hybrid compounds.
[0021] FIG. 3B is a synthetic scheme for various phenyl substituted diphenylfuran alkyloxy linker hybrid compounds.
[0022] FIG. 3C is a synthetic scheme for various phenyl substituted diphenylfuran alkyloxy linker hybrid compounds.
[0023] FIG. 3D is a prophetic synthetic scheme for various diphenylfuran alkyloxy linker hybrid compounds.
[0024] FIG. 4 is a prophetic synthetic scheme for various alkyl amide linker hybrid compounds. [0025] FIG. SA is a prophetic synthetic scheme for various phenylalkyl linker hybrid compounds 8a and 8b.
[0026 J FIG. SB is a synthetic scheme for various phenylalkyl linker hybrid compounds.
[0027] FIG. 6A is a synthetic scheme for various unsubstituted and substituted biphenyl linker a ti -parasitic compounds.
[0028] FIG. 63B is a synthetic scheme for various substituted biphenyl tinker antiparasitic compounds.
[0029] FIG. 6C is a synthetic scheme for various substituted biphenyl linker antiparasitic compounds.
[0030] FIG. 6D is a synthetic scheme for various substituted biphenyl linker antiparasitic compounds.
[0031 ] FIG. 7A is a synthetic scheme for various phenyl-piperazinyl-phenyl linker antiparasitic compounds.
10032] FIG. 7B is a synthetic scheme for various phenyl-piperazinyl linker anti-parasitic compounds.
[0033] FIG. 8A is a table reciting IC50 values of various phenoxyalkyl linker compounds against L. donovani, CC50 values against J774 macrophages, and CC50 values against HepG2.
[0034] FIG. 8B is a table reciting IC50 values of various diphenyifuran alkyloxy linker compounds against L. donovani, CC50 values against J774 macrophages, and CC50 values against HepG2.
[0035] FIG. 8C is a table reciting IC50 values of various biphenyl alkyloxy linker compounds against L. donovani, CC50 values against J774 macrophages, and CC50 values against HepG2.
[0036] FIG. 8D is a table reciting IC50 values of various piperazinyi linker compounds against L. donovani and CC50 values against J774 macrophages.
DETAILED DESCRIPTION
[0037] In various embodiments, a compound is provided, represented by Structural
Formula (la):
(la) Ar— C(=NR1)NR2— A— X— Y— Het2
and pharmaceutically acceptable salts thereof. Ar may be an optionally substituted aryl or nitrogen-containing heteroaryi. Rf and R2 may independently be H, optionally substituted CrC6 alkyl, or optionally substituted C3-C6 cycioalkyl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycioalkyl, heterocvcloalkyl, and heteroaryi. X may be O, S, amide, or a bond. Y may be optionally substituted C1-C 14 alkyl or optionally substituted C2-C14 alkenyl, e.g., optionally substituted Ci-Cio alkyl or optionally substituted C2-Cio alkenyl, or optionally substituted Cj-Cg alkyl or optionally substituted CVCg alkenyl. Met2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1 , 2, or 3 ring heteroatoms.
[0038] In some embodiments, a compound is provided, represented by Structural
Formula (I):
(I) Het1— C^NR^NR2— A— X— Y— Het2
and pharmaceutically acceptable salts thereof. Het1 may be an optionally substituted, nitrogen- containing heteroar}'!. R! and R may independently be H, optionally substituted Ci-CV, alkyl, or optionally substituted C3-C6 cycloalkyl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, lieterocycloalkyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted CI-CH alkyl or optionally substituted C2-C14 alkenyl, e.g., optionally substituted C 1 -C10 alkyl or optionally substituted C2-C 10 alkenyl , or optionally substituted Cj-Cg alkyl or optionally substituted C2-Cg alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
[0039] In several embodiments, the compound represented by Structural Formula (la) or
(I) may exclude certain compounds. For example, the compound represented by Structural Formula (la) or (I) may exclude free-base (neutral or non-salt) forms of Compounds la-f, wherein: Het3 is unsubstituted pyrid-2-yl; R1 and R2 are each H; X is O; Y is unbranched, unsubstituted C2-C4 alkyl; and Het2 is unsubstituted imidazole- 1 -yl or unsubstituted 1 , 2, 4 triazol-2-yl:
Figure imgf000010_0001
Figure imgf000011_0001
10040] In several embodiments, the compound represented by Structural Formula (la) or
(I) may include pharmaceutically acceptable salts of Compounds la-f. The compound represented by Structural Formula (la) or (I) may exclude free-base forms of Compounds la-f and pharmaceutically acceptable salts of Compounds la-f. The compound represented by Structural Formula (la) or (I) may exclude protonated forms of Compounds la-f.
[0041 ] In some embodiments, the compound represented by Structural Formula (la) or
(I) may exclude compounds wherem Het5 is one of unsubstituted pyridyl and pyrid-2-yl substituted with methyl or ethyl, for example, when: R! and R2 are each H; X is O; Y is unbranched, unsubstituted C2-C4 alky] ; and Het2 is unsubstituted imidazole- ! -yl or unsubstituted 1 ,2,4-triazol-2-yl. In some embodiments, the compound represented by Structural Formula (la) or (1) may exclude compounds wherein one of R1 and R2 is H and the other is methyl or ethyl, for example, when: Het1 is unsubstituted pyrid-2-yl; X is O; Y is unbranched, unsubstituted C2- C¾ alkyl; and Het" is unsubstituted imidazole- 1 -yl or unsubstituted l,2,4-triazol-2-yl. In some embodiments, the compound represented by Structural Formula (la) or (I) may exclude compounds wherem X is S, for example, when: Het1 is unsubstituted pyrid-2-yl; R1 and R2 are each H; Y is unbranched, unsubstituted C2-C4 alkyl; and Het2 is unsubstituted imidazole-l -yl or unsubstituted l,2,4-triazoi-2-yl. In some embodiments, the compound represented by Structural Formula (la) or (1) may exclude compounds wherein Y is C2-C4 alkyl substituted with methyl or ethyl, unsubstituted or methyl substituted C1-C5 alkyl, or unsubstituted Ci-Ce alkyl, for example, when: Het1 is unsubstituted pyrid-2-yl; R1 and R2 are each H; X is O; and Het2 is unsubstituted imidazole-l-yl or unsubstituted l ,2,4-triazol-2-yl. In some embodiments, the compound represented by Structural Formula (la) or (I) may exclude compounds wherein Het2 is one of: methyl or ethyl substituted imidazole-l -yl; unsubstituted imidazolyl; methyl or ethyl substituted imidazolyl; methyl or ethyl substituted l,2,4-triazol-2-yl; unsubstituted 1 ,2,4-triazolyl; methyl or ethyl substituted 1,2,4-triazolyl; unsubstituted triazolyl; and methyl or ethyl substituted triazolyl; for example, when: Het1 is unsubstituted pyrid-2-yl; R1 and R2 are each H; X is O; and Y is unbranched, unsubstituted C2-C4 alkyl.
[0042] In several embodiments, Het1 may be optionally substituted pyridyl, pyrazinyl, pyrimidinyl, or pyridizinyl. For example, Het1 may be optionally substituted pyridyl. The compound may be represented by Structural Formula (II): C(=NR1 )NR2— A-X-Y— Het2
100431 In several embodiments, the compound may be represented by Structural Formula
NH
Het N— A— X— Y— Het
H
[0044] in various embodiments, each ring in the optionally substituted linking moiety- represented by A may be independently and optionally substituted by one or more of: hydroxy, halo, and C]~Ct, alkoxy. A may include an optionally substituted heteroaryl or optionally substituted heterocycloalkyl ring. A may include an optionally substituted, oxygen-containing, heteroaryl or heterocycloalkyl ring. A may include an optionally substituted furanyi or optionally substituted ietrahydrofuranyl ring. A may include optionally substituted 2,5-furanyl. A may include one or two optionally substituted phenyl ring A may include optionally substituted 1.4-phenyl. A may be optionally substituted 1 ,4-phenyl. A may be optionally substi luted pheny 1 -heteroaryl -phenyl .
[0045] For example, the compound of Structural Formula III may be represented by one of Structural Formulas Illa)-(IIIf):
Figure imgf000012_0001
wherein Z, Z1, and Z2 are each independently CH or N, n may be 1-14, e.g., 1-10, and RJ may represent H, halogen, optionally halogenated Ci-Cf, alkyl, or optionally halogenated Ci-Cf, alkoxy.
Figure imgf000013_0001
Figure imgf000014_0001
[0047] The compound may be, for example, represented by Structural Formula above, e.g., compound 14
Figure imgf000014_0002
100481 In some embodiments, the compound may be represented by Structural Formula
Figure imgf000014_0003
wherein each RJ may independently represent H, halogen, optionally halogenated Cj-C6 alkyl optionally halogenated Ci-C6 alkoxy. For example, the compound may be represented by Structural Formula (V):
Figure imgf000014_0004
[0049] In several embodiments. Y may include at least 4 linking atoms between X and
Het2. X may be O or a bond and Y may be Ci-Cw, e.g.. Ci-Cio alkyl optionally substituted with one or more of: optionally halogenated C-.-Cs alkyl and optionally halogenated aryl. [0050] For example, the compound may be represented by one of Structural Formulas
(Va)-(Ve), wherein each Z Z1, and Z " are independendv CH or N:
Figure imgf000015_0001
wherein Z. Z and Z2 are each independently CH or . n may be 1-14, e.g.. 1-10, and R* may represent H, halogen, optionally halogenated CrC6 alkyl, or optionally halogenated Ci-C6 alkoxy.
[0051 ] For example, in some embodiments, the compound may be represented by
Structural Formula VI I ):
Figure imgf000015_0002
wherein: Z may be CH or N; each R3 may independently be H, halogen, optionally halogenated Ci-Cio alkyl, or optionally halogenaied Ci-Ci alkoxy; and si may be an integer from 1 to 10. For example, the compoimd may be one of Compounds 2a-2h:
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
[0054] The compound may be, for example, represented by Stmctural Formula (Vd) above, e.g., one of compounds 13a-13c:
Figure imgf000020_0002
Figure imgf000021_0001
Figure imgf000021_0002
wherein R4 may be H, optionally halogenated CVCJO alkyl, or optionally halogenated aryl. The compound may be represented by Structural Formula (Vlb):
NH O R4
(Vlb) H H
[0056] In some embodiments, Het2 may include an optionally substituted one of: pyrrole, diazole, thiadiazole, oxadiazole, and tnazole. For example, Het2 may be optionally substituted imidazole or optionally substituted 1, 2, 4 triazole,
[0057] In several embodiments, the compound may be represented by Structural Formula
(VIII):
Figure imgf000021_0003
wherein: each R5 may independently be H, halogen, C]~C4 alkyl, or C1-C4 alkoxy; and R6 may be H, optionally halogenated C-.-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl For example, the compound may be one of Compounds 5a-5f:
5a
Figure imgf000021_0004
Figure imgf000022_0001
Figure imgf000023_0001
In various embodiments, the compound may be represented by Structural Formula
Figure imgf000023_0002
wherein: each Rs may independently be H, halogen, C1-C alkyl. or C1-C4 alkoxy; and R" may¬ be H, optionally haiogenated CrC6 alkyl, optionally halogenated phenyl, or optionally halogenated bi phenyl. For example, the compound may be one of Compounds 6a-6f:
Figure imgf000023_0003
Figure imgf000024_0001
0059] In some embodiments, the compound may be represented by Structural Formula
Figure imgf000024_0002
wherein: each Rs may independently be H, halogen, C C4 alkyl, or C1-C4 alkoxy; and R" may¬ be H. optionally halogenated C;-C6 alkyl, optionally halogenated phenyl, or optionally halogenaied biphenyl. For example, the compound may be one of Compounds 7a-7f:
Figure imgf000025_0001
ί 0060] in several embodiments, the compound may be represented by Structural Formula
H
Figure imgf000025_0002
wherein: each R5 may independently be H, halogen, C1-C4 alkyl, or C1-C4 alkoxy; and R6 may be H, optionally halogenated C : -C6 alkyl, optionally halogenated phenyl, or optionally halogenated bi phenyl,
[0061 j in several embodiments, the compound may be represented by Structural Formula
Figure imgf000026_0001
wherem: Rs may independently be H, halogen, CrC4 alkyl, or C1-C4 alkoxy; and R6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenated phenyl, or optionally halogenated bi phenyl .
[0062] In several embodiments of the compound represented by Structural Formula (la) or (I), A may be phenyl and X may be a bond. For example, the compound may be represented by Structural Formula (XIII):
Figure imgf000026_0002
wherein Z may be CH or N; and si may be an integer from 1 to 10. For example, the compound may be one of Compounds 8a-8b:
Figure imgf000026_0003
[0063] In several embodiments of the compound represented by Structural Formula (la) or (I), A may be a bond. For example, the compound may be represented by Structural Formula
Figure imgf000026_0004
wherein Z may be CH or N; and n may be an integer from 1 to 10. For example, the compound may be one of Compounds 9a-9d, e.g., 9a-9c:
Figure imgf000026_0005
0064] In several embodiments of the compound represented by Structural Formula (la) or (Ϊ). A may be optionally substituted biphenyl. For example, the compound may be represented by Structural Formula XV):
Figure imgf000027_0001
. ., one of (XVa
Figure imgf000027_0002
wherein Z, Z and Z1 are each independently CH or N, n may be 1-14, e.g., 1- 10, and R3 may- represent H, halogen, optionally halogenated Cj-C6 alkyl, or optionally halogenated Cj-C6 alkoxy.
[0065] For exam le, the compound may be one of Compounds 10a~10n:
Figure imgf000027_0003
Figure imgf000028_0001
Figure imgf000029_0001
10066] In several embodiments of the compound represented by Structural Formula (la) or (I), A may be optionally substituted phenyl-piperazinyl-phenyl. For example, the compound may be represented by one of Structural Formulas XVI) and (XVII):
Figure imgf000030_0001
For example, the compounds may be represented by one of (XVIa)-(XVIb):
Figure imgf000030_0002
wherein Z, Z!, and Z" are each independently CH or N, n may be 1- 14, e.g., 1-10, and R3 may- represent H, halogen, optionally halogenated Cj -C6 alkyl, or optionally halogenated Cj -C6 alkoxy . For example, the compound may be one of Compounds lla-l ld:
Figure imgf000030_0003
Figure imgf000031_0001
Further, for example, the compounds may be represented by one of (XVIIa)-(XVIIb):
d (XVIIb)
Figure imgf000031_0002
wherein Z, Z1, and Z2 are each independently CH or N, n may be 1-14, e.g., 1-10, and RJ may represent H, halogen, optionally halogenated Ci~C6 alk l, or optionally halogenated Ci~C6 alkoxy. For example, the compound may be Compound 12a:
[0067] in various embodiments, a method of anti-parasitic treatment is provided. The method may include providing a subject that is infected by or at risk of infection by a parasite. The method may include administering a compound to the subject in an amount effective to mitigate infection by the parasite in the subject.
[0068] 'The compound of the method may be represented by Structural Formula (la):
(la) Ar— C (=NR! )NR2— A— — Y— Het2
and pharmaceutically acceptable salts thereof. Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl. R1 and Rz may independently be H, optionally substituted Ci-Ce alkyl, or optionally substituted C C , cycloalkvl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkvl, heterocycloalkyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted C1-C14 alkyl or optionally substituted C2-C 14 alkenyl, e.g., optionally substituted C-.-Cio alkyl or optionally substituted C2-C 30 alkenyl, or optionally substituted Ci-Cg alkyl or optionally substituted C2-C8 alkenyl. Het2 may be an
9Q optionally substituted five-membered nitrogen -containing heteroaromatic ring comprising ! , 2, or 3 nng heteroatoms,
[0069] The compound of the method may be represented by Structural Formula (1):
(I) Het1— C(=NR1)NR2— A— X— Y— Het2
and pharmaceutically acceptable salts thereof. Het3 may be an optionally substituted, nitrogen- containing heteroaryi. R1 and R2 may independently be H, optionally substituted Cj-Ce alkyl, or optionally substituted C3-C6 cycloalkyl. A may be a bond or an optionally substituted Unking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: ary , cycloalkyl, heterocycloalkyl, and heteroaryi. X may be O, S, amide, or a bond. Y may be optionally substituted Ci-Cu alkyl or optionally substituted C2-C 14 alkenyl, e.g., optionally substituted Ci-Cio alkyl or optionally substituted C2-C10 alkenyl, or optionally substituted Ci~Cg alkyl or optionally substituted C2-Cg alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising I, 2, or 3 ring heteroatoms.
[0070] In some embodiments, the method may include administering the compound represented by Structural Formula (la) or (I) in the form of any pharmaceutical composition described herein.
[0071] In several embodiments of the method, when the parasite is L. amazonensis , the compound represented by Structural Formula (la) or (I) may exclude free-base forms of Compounds la-f. The compound represented by Structural Formula (la) or (I) may exclude protonated forms of Compounds la-f.
[0072] In some embodiments, the subject may be infected by the parasite, and the method may include administering the compound to the subject in an amount effective to mitigate one or more symptoms of infection by the parasite in the subject. Alternatively or in addition, the subject may be at risk of infection by the parasite. The method may include administering the compound to the subject in an amount effective to mitigate infection or reinfection of the subject by the parasite.
[ 0073] In several embodiments, the parasite may be a kinetoplastid. In various embodiments, the parasite may belong to the genus Leishmcmia. The Leishmama parasite may be, for example, one of: L. aethiopica, L. amazonensis, L. arabica, L. archibaldi, L. aristedesi, L. Viannia, L. braziliensis, L. chagasi, L, colombiensis, L. deanei, L. donovani, L. enriettii, L, eq atorensis, L. forattinii, L. garnhami, L. gerbili, L. guyanensis, L. herreri, L. hertigi, L. infantum, L. killicki, L. lainsoni, L. major, L. mexicana, L. naijfi, L. panamensis, L. peruviana, L. pifanoi, L, shawi, L. tarentolae, L, tropica, L, turanica, and L. venezuelensis . The subject may suffer from or may be at risk of one or more of: cutaneous leishmaniasis, mucocutaneous leishmaniasis, and visceral leishmaniasis. The subject may be a human, dog, cat, cow, horse, sheep, pig, bird, amphibian, or fish, e.g., a mammal such as a human.
[00741 In some embodiments, the parasite may belong to the genus Trypanosoma. The
Trypanosoma parasite may be, for example, one of: T. amhystomae, T. avium, T. boissoni, T. brucei, T. cruzi, T, congolense, T, equinum, T eqwperdum, T. evansi, T. everetti, T. hosei, T. irwini, T. lewisi, T. melophagium, T. paddae, T. parroti, T. percae, T. rangeli, T. rotatorium, T. rugosae, T. ser genii, T. simiae, T. simper cae, T. suis, T. theileri, T. triglae, and T. vivax. The subject may suffer from or may be at risk of one or more of: Africa trypanosomiasis, sleeping sickness, Chagas disease, nagana, and surra. The subject may be a human, dog, cat, cow, horse, sheep, pig, bird, amphibian, or fish, e.g., a mammal such as a human.
[0075 J in several embodiments of the method, when the parasite is L. amazonensis, the compound represented by Structural Formula (la) or (I) may exclude free-base forms of Compounds la-f. The compound represented by Structural Formula (la) or (I) may exclude protonated forms of Compounds la-f. Further, for example, the compound represented by Structural Formula (la) or (I) in the method may exclude each of free-base Compounds la-f when the parasite is one of L. donovani, L. amazonensis, and L. major. For example, the method may exclude each of free-base Compounds la-f when the parasite is of the genus Leishmania, for example, one of: L. aeihiopica, L. amazonensis, L. arabica, L. archibaldi, L. arisiedesi, L. Viarmia, L. braziliensis, L. chaga i, L. colomhiensis, L. deanei, L. donovani, L. enriettii, L. equator ensis, L. forattinii, L. garnhami, L. gerbiii, L. guyanensis, L. herreri, L. hertigi, L. infantum, L. kiUicki, L. lainsoni, L. major, L. mexicana, L. naijji, L. panamensis, L. peruviana, L. pifanoi, L. shawi, L. tarentolae, L. tropica, L. turanica, and L. venezuelensis . The method may exclude each of free-base Compounds la-f when the subject suffers from visceral leishmaniasis.
[0076] In several embodiments of the method, the compound represented by Structural
Formula (la) or (I) may exclude each of free-base Compounds la-f when the parasite is T. brucei or T. cruzi. For example, the method may exclude each of free-base Compounds la-f when the parasite is of the genus Trypanosoma, for example, one of: T. ambysiomae, T. avium, T. boissoni, T. brucei, T. cruzi, T. congolense, T. equinum, T. equiperdurn, T. evansi, T. everetti, T. hosei, T. irwini, T. lewisi, T. melophagium, T. paddae, T. parroti, T. percae, T. rangeli, T. rotatorium, T. rugosae, T. sergenti, T. simiae, T. sinipercae, T. suis, T. theileri, T. triglae, and T. vivax. In various embodiments of the method, each of the preceding parasite-based exclusions may be independently applied in corabinaiion with any of the various embodiments described herein as excluding certain compounds represented by Structural Formula (la) or (1). [0077] In some embodiments of the method, the method may incorporate any of the various embodiments described herein for excluding certain compounds represented by Structural Formula (la) or (I). For example, the compound represented by Structural Formula (la) or (I) may exclude free-base (neutral or non-salt) forms of Compounds la-f. The compound represented by Structural Formula (la) or (I) may include pharmaceutically acceptable salts of Compounds la-f. The compound represented by Structural Formula (la) or (I) may exclude free-base forms of Compounds la-f and pharmaceutically acceptable salts of Compounds la-f. The compound represented by Structural Formula (la) or (I) may exclude protonated forms of Compounds la-f.
[0078] In several embodiments of the method, the compound may include any aspect of the compounds represented by Structural Formulas (la) or (I) as described herein. For example, the compounds of the method may be represented by, as described herein, any one of, or any group of, Structural Formulas: (1), (la), (II), (III), (Ilia), (1Mb), (Illc), (Hid), (Hie), (Illfj, (IV), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Via), (VIb), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVa), (XVb), (XVc), (XVI), (XVIa), (XVIb), (XVII), (XVIIa), and (XVIIb). Further, for example, the compound may be any one of, or any group of, as described herein, Compounds: la-lv; 2a-2h: 3a-3g; 4a-4m; 5a-5f; 6a-6f; 7a-7f; 8a-8b; 9a-9d; lOa-lOe; l la-lld; 12a; 13a- 13c; and 14a.
[00791 For example, in some embodiments of the method, the compounds represented by-
Structural Formulas (la) or (I) may exclude compounds wherein Het1 is one of unsubstituted pyridyl and pyrid-2-yl substituted with methyl or ethyl, for example, when: R1 and R are each H; X is O; Y is unhranched, unsubstituted C2-C10 alkyl; and Het2 is unsubstituted imidazole- 1 -yl or unsubstituted 1, 2, 4 triazol-2-yl. In some embodiments, the compound represented by Structural Formula (la) or (I) may exclude compounds wherein one of R3 and R2 is H and the other is methyl or ethyl, for example, when: Het1 is unsubstituted pyrid-2-yl; X is O; Y is unbranched, unsubstituted C2-C10 alkyl; and Hef is unsubstituted imidazole-l-yl or unsubstituted 1 , 2, 4 triazol-2-yl. In some embodiments, the compound represented by Structural Formula (la) or (I) may exclude compounds wherein X is S, for example, when: Het1 is unsubstituted pyrid-2-yl; R1 and R2 are each H; Y is unbranched, un substituted C2-C10 alkyl; and Het2 is unsubstituted imidazole-l-yl or unsubstituted 1 , 2, 4 triazol-2-yl. In some embodiments, the compound represented by Structural Formula (la) or (1) may exclude compounds wherein Y is C2-C4 alkyl substituted with methyl or ethyl, unsubstituted or methyl substituted C1-C5 alkyl, or unsubstituted Ci-Ce alkyl, for example, when: Het1 is unsubstituted pyrid-2-yl; R1 and R2 are each H; X is O; and Het2 is unsubstituted imidazole-l -yl or unsubstituted 1, 2, 4 triazol-2-yl. In some embodiments, the compoimd represented by Structural Formula (la) or (I) may exclude compounds wherein Het2 is one of: methyl or ethyl substituted imidazole-l-yl; unsubstituted imidazolyl; methyl or ethyl substituted imidazolyl; methyl or ethyl substituted l,-2,-4-triazol-2- yl; unsubstituted 1 ,-2,-4-triazolyl; methyl or ethyl substituted 1,-2,-4-triazolyl; unsubstituted triazolyl; and methyl or ethyl substituted triazolyl ; for example, when: Het1 is unsubstituted pyrid-2-yl: R1 and R are each H: X is O; and Y is unbranched, unsubstituted C2-C4 alkyl.
10080] In several embodiments of the method, Het1 may be optionally substituted pyridyl, pyrazinyl, pyrimidinyl, or pyndizinyl. For example, Het1 may be optionally substituted pyridyl. The compound of the method may be represented by Structural Formula (II). The compound of the method may be represented by Structural Formula (III). In several embodiments of the method, Y may include at least 4 linking atoms between X and Het2. X may be O or a bond and Y may be C1-C14, e.g., C1-C10 alkyl optionally substituted with one or more of: optionally halogenated Cj-Cs alkyl and optionally halogenated aryl. For example, the compound may be one of Compounds la-n. The compound of the method may be represented by any of Structural Formulas (Ilia), (IHb), (IIIc), (Hid), (Hie), and (Hlf), wherein Z, Z and 7 ' may be each independently CH or N, n may be 1-14, and R3 may be H, halogen, optionally halogenated CVC6 alkyl, or optionally halogenated C-. -Ce alkoxy. The compound of the method may be any one of Compounds la-lv. The compound of the method may be any one of Compounds la-ln.
[0081] In various embodiments of the method, each ring in the optionally substituted linking moiety represented by A may be independently and optionally substituted by one or more of: hydroxy, halo, and Ci-C io , e.g., Ci-Cs alkoxy. A may include an optionally substituted heteroaryl or optionally substituted heterocycloalkyl ring. A may include an optionally substituted, oxygen-containing, heteroaryl or heterocycloalkyl ring. A may include an optionally substituted furanyl or optionally substituted tetrahydrofuranyl ring. A may include optionally substituted 2,5-furanyl. A may include one or two optionally substituted phenyl rings. A may include optionally substituted 1 ,4-phenyl. A may be optionally substituted 1,4-phenyl. A may¬ be optionally substituted phenyl-heteroaryl-phenyl.
[0082] In some embodiments of the method, the compound may be represented by
Structural Formula (IV), wherein each R3 may independently represent H, halogen, optionally halogenated Ci-C6 alkyl, or optionally halogenated Ci-C6 alkoxy. The compound may be represented by Structural Formula (V). The compound of the method may be represented by any of Structural Formulas (V), (Va), (Vb), (Vc), (Vd), and (Ve), wherein Z, Z1, and Z2 may be each independently CH or N, n may be 1 -14, and R3 may be H, halogen, optionally halogenated Ci-C , alkyl, or optionally halogenated C i-Cr, alkoxy,
[0083] In various embodiments of the method, the compound may be represented by
Structural Formula (Via) wherein R4 may be H, optionally halogenated Ci-Cg alkyl, or optionally halogenated aryl. The compound may be represented by Structural Formula (VIb), 10084] In some embodiments of the method, Het2 may include an optionally substituted one of: pyrrole, diazole, thiadiazole, oxadiazole, and triazole. For example, Het2 may be optionally substituted imidazole or optionally substituted 1 , 2, 4 triazole. For example, the compound may be represented by Structural Formula (VII), wherein: Z may be CH or N; each R3 may independently be H, halogen, optionally halogenated Ci-C6 alkyl, or optionally halogenated C1-C0 alkoxy; and n may be an integer from 1 to 10. For example, the compound may be one of Compounds 2a~2g. The compound may be, for example, one of Compounds 3a- 3g. The compound may be, for example, one of Compounds 4a-4m, e.g., 4a-4i. The compound may be, for example, one of Compounds 13a-13c.
[0085] In several embodiments of the method, the compound may be represented by
Structural Formula (VIII), wherein each R3 may independently be H, halogen, Ci~C4 alkyl, or C j- 14 alkoxy, and R6 may be H, optionally halogenated CrC6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl. For example, the compound may be one of Compounds 5a-5f. The compound may be represented by Structural Formula (IX), wherein: each R5 may independently be H, halogen, Cj - alkyl, or Cj - alkoxy; and R6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl . For example, the compound may be one of Compounds 6a-5f. The compound may be represented by Structural Formula (X) wherein: each R5 may independently be H, halogen, Ci~ C4 alkyl, or C1-C4 alkoxy; and ll6 may be H, optionally halogenated CrC6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl. For example, the compound may be one of Compounds 7a-7f.
[0086] In several embodiments of the method, the compound may be represented by
Structural Formula (XI), wherein each Rs may independently be H, halogen, C1-C4 alkyl, or Ci- C4 alkoxy; and R6 may be H, optionally halogenated i-C alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
[0087] In several embodiments of the method, the compound may be represented by
Structural Formula (XII), wherein each Rs may independently be H, halogen, C1-C4 alkyl, or Ci- C4 alkoxy; and R6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenaied phenyl, or optionally halogenated biphenyl. [0088] In several embodiments of the method, the compound may be represented by
Structural Formula (la) or (I), wherein A may be phenyl and X may be a bond. For example, the compound may be represented by Structural Formula (XIII), wherein Z may be CH or N; and n may be an integer from 1 to 10. For example, the compound may be one of Compounds 8a-8b.
[0089] In several embodiments of the method, the compound may be represented by
Structural Formula (la) or (I), wherein A may be a bond. For example, the compound may be represented by Structural Formula (XIV), wherein Z may be CH or N; and n may be an integer from 1 to 10. For example, the compound may be one of Compounds 9a-9d, for example, 9a-9c.
[0090] In several embodiments of the method, the compound may be represented by
Stmctural Formula (XV), wherein Z, Zf , and Z2 may be each independently CH or , n may be 1-14, and R3 may be H, halogen, optionally halogenated Ci-Ce alkyl, or optionally halogenated CrCe alkoxy. For example, the compound may be represented by one of Structural Formulas (XVa)-(XVc). For example, the compound may be one of Compounds 10a- 10η.
[0091 ] In several embodiments of the method, the compound may be represented by one of Structural Formulas (XVI) and (XVII), wherein Z, Z and Z2 may be each independently CH or N, n may be 1-14, and R' may be H, halogen, optionally halogenated Ci-Cr, alkyl, or optionally halogenated Ci-C6 alkoxy. For example, the compound may be represented by one of Structural Formulas (XVIa)-(XVIb), e.g., the compound may be one of Compounds lla-lld.
[0092] In various embodiments, a pharmaceutical composition is provided. The pharmaceutical composition may include a pharmaceutically acceptable carrier or excipient.
[0093] The pharmaceutical composition may include a compound represented by
Structural Formula (la):
(la) Ar— C(=NR1)NR2— A— X— Y— Het2
and pharmaceutically acceptable salts thereof. Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl. R1 and R2 may independently be H, optionally substituted C1-C5 alkyl, or optionally substituted C3-C6 cycloalkyl. A may be a bond or an optionally substituted linking moiety comprising I, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycioalkyi, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted C 1-C 14 alkyl or optionally substituted C2-C 14 alkenyl, e.g., optionally substituted Cj-Cio alkyl or optionally substituted C2-Cio alkenyl, or optionally substituted Cj-Cg alkyl or optionally substituted C?-CB alkenyl. Met2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms. [0094] The pharmaceutical composition may include a compound represented by
Structural Formula (I):
(1) Het1— C(=NR1)NR2— A— X— Y— Het2
and pharmaceutically acceptable salts thereof. Het1 may be an optionally substituted, nitrogen- containing heteroaryl. R1 and Rz may independently be H, optionally substituted C]-Ce alkyl, or optionally substituted C3-CV, cycloalkyl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted C1-C14, e.g., Cj-Cio alkyl or optionally substituted C2-C 14, e.g., Cj-C-.o alkenyi. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1 , 2, or 3 ring heteroatoms.
[0095] In several embodiments of the pharmaceutical composition, the compound represented by Structural Formula (la) or (1) may include one of Compounds la-f. In some embodiments, each of Compounds la-f may be in the form of a solid. Additionally or alternatively, each of Compounds la~f may be in the form of a pharmaceutically acceptable salt. Additionally or alternatively, at least a portion of the pharmaceutically acceptable carrier or excipient may be in the form of a solid or gel. Additionally or alternatively, the pharmaceutical composition may be configured for administration in unit dosage form. Additionally or alternatively, the pharmaceutical composition may be configured for administration in the form of one of: a tablet; a capsule; a lozenge; a cream, a spray, a transdermal patch, an aerosol, a suppository, a depot preparation; a suture that is coated or impregnated with one of Compounds la-f; a bandage that is coated or impregnated with one of Compounds la-f; a medical device that is coated or impregnated with one of Compounds la-f; and the like.
[0096] In some embodiments of the pharmaceutical composition, pharmaceutically acceptable salts of Compounds la- If are included. In some embodiments of the pharmaceutical composition, free-base (neutral) Compounds la-f may be excluded. In some embodiments of the pharmaceutical composition, protonated forms of Compounds la-lf may be excluded. Alternatively or in addition, the pharmaceutical composition may incorporate any of the various embodiments described herein for excluding certain compounds represented by Structural Formula (la) or (I). For example, the compound represented by Structural Formula (la) or (I) may exclude free-base (neutral or non-salt) forms of Compounds la-f. The compound represented by Structural Formula (la) or (I) may include pharmaceutically acceptable salts of Compounds la-f. The compound represented by Structural Formula (la) or (I) may exclude free-base forms of Compounds la-f and pharmaceutically acceptable salts of Compounds la-f. The compound represented by Stmctural Formula (la) or (I) may exclude protonated forms of Compounds la-f.
[0097] In several embodiments of the pharmaceutical composition, the compound may include any aspect of the compounds represented by Structural Formulas (la) or (I) as described herein. For example, the compounds of the pharmaceutical composition may be represented by, as described herein, any one of, or any group of, Structural Formulas: (1), (la), (II), (HI), (Ilia), (IIIf>), (IIIc), (Hid), (Hie), (Illi), (IV), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Via), (VIb), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVa), (XVb), (XVc), (XVI), (XVIa), (XVifo), (XVII), (XVIIa), and (XVIIb). Further, for example, the compound may be any one of, or any group of, as described herein, Compounds: la-lv; 2a-2h; 3a-3g; 4a-4m; 5a-5f; 6a-6f; 7a-7f; 8a-8b; 9a-9d; lOa-lOn; lla-lld; 12a; 13a-13c; and 14a.
[0098] For example, in some embodiments of the pharmaceutical composition, the compounds represented by Structural Formulas (la) or (I) may exclude compounds wherein Het5 is one of unsubstituted pyridyl and pyrid-2-yl substituted with methyl or ethyl, for example, when: R1 and R2 are each H; X is O; Y is unbranched, unsubstituted C2-C10 alky]; and Het2 is unsubstituted imidazole-! -yl or unsubstituted 1, 2, 4 triazol-2-yl. In some embodiments, the compound represented by Structural Formula (la) or (I) may exclude compounds wherein one of R1 and R is H and the other is methyl or ethyl, for example, when: Het1 is unsubstituted pyrid- 2-yl; X is O; Y is unbranched, unsubstituted C2-C10 alkyl; and Het2 is unsubstituted imidazole- ! - yl or unsubstituted I, 2, 4 tnazol-2-yi. In some embodiments, the compound represented by Structural Formula (la) or (I) may exclude compounds wherein X is S, for example, when: Het1 is unsubstituted pyrid-2-yl; R1 and R^ are each H; Y is unbranched, unsubstituted C2-C 10 alky] ; and Het2 is unsubstituted imidazole- 1-yl or unsubstituted ! , 2, 4 triazol-2-yl. In some embodiments, the compound represented by Structural Formula (la) or (I) may exclude compounds wherein Y is C2-C4 alkyl substituted with methyl or ethyl, unsubstituted or methyl substituted C1-C5 alkyl, or unsubstituted Ci-Ce alkyl, for example, when: Het1 is unsubstituted pyrid-2-yl: R1 and R2 are each H; X is O; and Het2 is unsubstituted imidazole- 1-yl or unsubstituted 1 , 2, 4 triazol-2-yl. In some embodiments, the compound represented by Structural Formula (la) or (I) may exclude compounds wherein Het2 is one of: methyl or ethyl substituted imidazole- 1-yl; unsubstituted imidazoly!; methyl or ethyl substituted imidazolyl; methyl or ethyl substituted l,-2,-4-triazol-2-yl; unsubstituted 1,-2,-4-triazolyl; methyl or ethyl substituted 1,-2,- 4-triazoiyl; unsubstituted triazolyl; and methyl or ethyl substituted triazolyl; for example, when: Het1 is unsubstituted pyrid-2-yl; R1 and R are each H; X is O; and Y is unbranched, unsubstituted C2-C4 alkyl. [0099] In several embodiments of the pharmaceutical composition, Het may be optionally substituted pyridyl, pyrazinyl, pyrimidinyl, or pyridizinyl For example, Het5 may be optionally substituted pyridyl. The compound of the pharmaceutical composition may be represented by Structural Formula (II), The compound of the pharmaceutical composition may be represented by Structural Formula (III). In several embodiments of the pharmaceutical composition, Y may include at least 4 linking atoms between X and Met2. X may be O or a bond and Y may be C-. -CH, e.g., C-.-Cio alkyl optionally substituted with one or more of: optionally halogenated Ci-C alkyl and optionally halogenated aryl. For example, the compound may be one of Compounds la-n. The compound of the pharmaceutical composition may be represented by any of Structural Formulas (Ilia), (Illb), (Hie), (Hid), (Hie), and (Illf), wherein Z, Zf , and Z may be each independently CH or N, n may be 1-14, and RJ may be H, halogen, optionally halogenated Ci-C6 alkyl, or optionally halogenated C]-C6 alkoxy. The compound of the pharmaceutical composition may be any one of Compounds la-lv. The compound of the pharmaceutical composition may be any one of Compounds la-ln.
[00100] In various embodiments of the pharmaceutical composition, each ring in the optionally substituted linking moiety represented by A may be independently and optionally substituted by one or more of: hydroxy, halo, and CJ -CJO , e.g., C-.-Ce alkoxy. A may include an optionally substituted heteroaryl or optionally substituted heterocycloalkyl ring. A may include an optionally substituted, oxygen-containing, heteroaryl or heterocycloalkyl ring. A may include an optionally substituted furanyl or optionally substituted tetrahydrofuranyl ring. A may include optionally substituted 2,5 -furanyl. A may include one or two optionally substituted phenyl rings. A may include optionally substituted 1,4-phenyl. A may be optionally substituted 1 ,4-phenyl. A may be optionally substituted phenyl-heteroaryl-phenyl.
[00101 J In some embodiments of the pharmaceutical composition, the compound may be represented by Structural Formula (IV), wherein each R3 may independently represent H, halogen, optionally halogenated Ci-Ce alkyl, or optionally halogenated Ci-Cf, alkoxy. The compound may be represented by Structural Formula (V). The compound of the pharmaceutical composition may be represented by any of Structural Formulas (V), (Va), (Vb), (Vc), (Vd), and (Ve), wherein Z, Z1, and 7s may be each independently CH or N, n may be 1-14, and RJ may be H, halogen, optionally halogenated Ci-Ce alkyl, or optionally halogenated Ci-Ce alkoxy.
[00102] In various embodiments of the pharmaceutical composition, the compound may be represented by Structural Formula (Via) wherein R4 may be H, optionally halogenated C-.-Cs alkyl, or optionally halogenated aryl. The compound may be represented by Structural Formula (Vlb). [00103] In some embodiments of the pharmaceutical composition, Met2 raay include an optionally substituted one of: pyrrole, diazole, thiadiazole, oxadiazole, and triazole. For example, Het2 may be optionally substituted imidazole or optionally substituted 1, 2, 4 triazole. For example, the compound may be represented by Stmctural Formula (VII), wherein: Z may be CH or N; each R3 may independently be H, halogen, optionally halogenated Cj-Ce alkyi, or optionally halogenated Cj-Ce alkoxy; and n may be an integer from 1 to 10. For example, the compound may be one of Compounds 2a-2g. The compound may be, for example, one of Compounds 3a-3g. The compound may be, for example, one of Compounds 4a-4m, e.g., 4a~4i. The compound may be, for example, one of Compounds 13a- 13c.
[00104] In several embodiments of the pharmaceutical composition, the compound may be represented by Stmctural Formula (VIII), wherein each R5 may independently be H, halogen, Ci-C4 alkyl, or C1-C4 alkoxy, and R6 may be H, optionally halogenated Ci-Ce alky , optionally halogenated phenyl, or optionally halogenated biphenyl. For example, the compound may be one of Compounds 5a-5f. The compound may be represented by Structural Formula (IX), wherein: each R5 may independently be H, halogen, C1-C4 alkyi, or C1-C4 alkoxy; and R6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl. For example, the compound may be one of Compounds 6a-Sf. The compound may be represented by Structural Formula (X) wherein: each R5 may independently be H, halogen, C1-C4 alkyl, or C1-C4 alkoxy; and R6 may be H, optionally halogenated Ci-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl. For example, the compound may be one of Compounds 7a-7f.
[00105] In several embodiments of the pharmaceutical composition, the compound may be represented by Structural Formula (XI), wherein each R5 may independently be H, halogen, -C4 alkyl, or Cj-C4 alkoxy; and R6 may be H, optionally halogenated C-.-Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
[00106] In several embodiments of the pharmaceutical composition, the compound may be represented by Stractural Formula (XII), wherein each R5 may independently be H, halogen, C-.-C4 alkyl, or C1-C4 alkoxy; and R6 may be H, optionally halogenated C Ce alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
[00107] In several embodiments of the pharmaceutical composition, the compound may be represented by Stmctural Formula (la) or (I), wherein A may be phenyl and X may be a bond. For example, the compound may be represented by Structural Formula (XIII), wherein Z may be CH or N; and n may be an integer from 1 to 10. For example, the compound may be one of Compounds 8a-8b. [00108] In several embodiments of the pharmaceutical composition, the compound may be represented by Structural Formula (la) or (I), wherein A may be a bond. For example, the compound may be represented by Structural Formula (XIV), wherein Z may be CH or N; and n may be an integer from 1 to 10. For example, the compound may be one of Compounds 9a~9d, for example, 9a~9c.
[00109] In several embodiments of the pharmaceutical composition, the compound may be represented by Structural Formula (XV), wherein Z, Z3, and Z2 may be each independently CH or N, n may be 1-14, and R3 may be H, halogen, optionally halogenated Ci- e alky], or optionally halogenated Ci-Ce alkoxy. For example, the compound may be represented by one of Structural Formulas (XVa)-(XVc). For example, the compound may be one of Compounds 10a- 10η.
[001 1 0] In several embodiments of the pharmaceutical composition, the compound may be represented by one of Structural Formulas (XVI) and (XVII), wherein Z, Z!, and Z2 may be each independently CH or N, n may be 1-14, and R' may be H, halogen, optionally halogenated Ci-C alkyl, or optionally halogenated i-C alkoxy. For example, the compound may be represented by one of Structural Formulas (XVIa)-(XVIb). For example, the compound may be one of Compounds lla-lld. Further, for example, the compound may be represented by one of Structural Formulas (XVIIa)-(XVIIb), e.g., the compound may be Compound 12a.
[0011 1 ] In various embodiments, a kit for anti-parasite treatment of a subject in need thereof is provided. The kit may include any anti-parasitic compound described herein, for example, the compound represented by Structural Formula (la):
(la) Ar— C(=NR1)NR2— A— X— Y— Het2
[001 12] and pharmaceutically acceptable salts thereof. Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl. R! and R2 may independently be H, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. I 'ach ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycioalkyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted Ci-C alkyl or optionally substituted (" ·-( j t alkenyl, e.g., optionally substituted -C10 alkyl or optionally substituted C2-C 10 alkenyl, or optionally substituted Ci-Cs alkyl or optionally substituted C2-C8 alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising I, 2, or 3 ring heteroatoms.
[00113] The kit may include any anti-parasitic compound described herein, for example, the compound represented by Structural Formula (I): (I) Het1— C(=NR1)NR2— A— X— Y— Het2
pharmaceutically acceptable salts thereof, and mixtures thereof with a pharmaceutically acceptable carrier or excipient to form a pharmaceutical composition. Het1 may be an optionally substituted, nitrogen-containing heteroaryl. 1 and R" may independently be H, optionally substituted Ci-C(s alkyl, or optionally substituted C3-C6 cycloalkyl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cy cloalkyl, heterocycloalkyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted C1-C 14, e.g., d~ do alkyl or optionally substituted d-d4, e.g., d- o alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms. The kit may include instructions. The instructions may direct a user to provide the subject, the subject being infected by a parasite or at risk of infection by the parasite. The instructions may direct a user to administer the compound or the pharmaceutical composition to the subject in an amount effective to mitigate infection by the parasite in the subject.
[00.1 14] In some embodiments of the kit, the compound represented by Structural Formula
(la) or (I) may include any aspect of the anti-parasitic compounds described herein, either alone or as encompassed by any of the methods or pharmaceutical compositions described herein.
[00115] In several embodiments of the kit, the instructions may direct a user to conduct any step or combination of steps described herein for the method.
EXAMPLES
Example 1 : Design Considerations and Molecular Modeling
[001 16] AIAs and antifungal azole drugs each include a nitrogen-containing heterocycle bound to a linear or curved linker. A known target of azole antifungal drugs is the CYP51 enzyme, which participates in sterol biosynthesis. The crystal structure of CYP51 from L. infantum has been reported in the form of a bound fluconazole molecule interacting with the heme portion of CYP51 through coordination of a triazole nitrogen with the heme iron atom. Such a structure is consistent with known crystal structures of other CYP51 -azole complexes, which also show a complex between the heme iron atom and the azole nitrogen. Although some azoles have been attempted in clinical treatment of leishmaniasis, azoles are less potent against Leishmania compared to T, cruzi in vitro.
[00117] Recent studies have uncovered inhibitors of kinetoplastid CYP51. The compound VNI (FIG. 1) binds with a ¾ of 70 nM to T. cruzi CYP51 and inhibits the growth of intracellular T. cruzi amastigotes by 50% at a concentration of 1.3 nM. (See Villalta, et al. "VNI cures acute and chronic experimental Chagas disease. " J. infect, Dis. 2013, 208, 504-511 , the entire contents of which are incorporated herein by reference) VNI also treats T. cruzi infections in murine models of Chagas disease. VNI has been crystallized with T. cruzi CYP51 and also coordinates via its imidazole nitrogen with CYP51 heme iron. A molecule similar to VNI, termed VNI/VNF (FIG. 1), is also a known inhibitor of L. infantum CYP51, although no studies against Leishmama parasites were reported.
[00118] Preliminary modeling calculations supported the binding of 5a and 6a to CYP51.
Accordingly, , the anti-parasitic compounds disclosed herein were designed by combining carefully selected AIA fragments and azole fragments. The disclosed anti -parasitic compounds were then synthesized and tested as detailed in the following Examples.
Example 2A: Synthesis of Pliesioxyalkyl Linker Anti-Parasitic Compounds
[00119] FIG. 2A is a synthetic scheme various phenoxyalkyl linker anti-parasitic
Compounds la-ln and Iv. Compounds la, lb, lc, le, If, lg, li, lm, and lv were made according to FIG. 2A. Generally, reagents and conditions for synthesis of compounds according to FIG. 2A included: a) α,ω-dibromoalkane, K2CO3, acetone; b) imidazole or 1,2,4-triazole, K2CO3, CH3CN; c) SnCl2.2H20, EtOAc; d) 5-(2-naphthylmethy])-2-pyridy thioimidate hydrobromide, CH3CN/EtOH (1 :3), rt.
[00120] Details of the representative synthesis of Compound le are as follows.
l-(4-bromobutoxy)-4-nitrobenze
Figure imgf000044_0001
[00121] Reaction of 4-nitrophenol (2.00 g, 14.4 mmol), 1,4-dibromobutane (3.5 ml., 6.33 g, 29.3 mmol), and potassium carbonate (5.96 g, 43.2 mmol) in acetone at reflux afforded l -(4- bromobutoxy)-4-nitrobenzene as white crystals, yield 1.69 g, 6.15 mmol, 43%; m.p. 39-42 °C. The T-l NMR spectrum of this material was consistent with that reported in Narlawar et al , Journal of Medicinal Chemistry. 2010, 53, 3028-3037.
4-(4-(lH-imidazol-l-yl)butoxy)aniline
Figure imgf000044_0002
[00122] Reaction of imidazole (0.44 g, 6.43 mmol), l-(4-bromobutoxy)-4-nitrobenzene
(1.20 g, 4.28 mmol), and potassium carbonate (0.89 g, 6.4 mmol) in acetonitrile at reflux afforded 1 -[4-(4-mtrophenoxy)butyl]- lH rnidazole as a dark brown solid, yield: 0.67 g, 2.6 mmol, 60%; m.p. 71-74 °C, lit m.p. 67-69 °C. The Ή NMR spectrum of this material was consistent with that reported in Salemo et. al, Bioorganic and Medicinal Chemistry, 2013, 21, 5145-5153, Reaction of l -[4-(4-nitrophenoxy)but 'l]-lH-imidazole (0.10 g, 0.38 mrnol) and stannous chloride dihydrate (0.43 g, 1.9 mrnol) in ethyl acetate at reflux afforded 4-(4-(lH- imidazol-l-yl)butoxy)aniline as a bright orange powder, yield: 0.046 g, 0.20 mrnol, 52%. Ή NMR (300 Ml 1/. DMSO-de): δ 1.57 (quint, J= 7.0, 2H), 1.82 (quint, J= 7.3, 2H), 3.81 it, J= 6.4, 2H), 4.00 (t, ,/ 7.0, 2H), 4.60 (br, 21 \ ) 6.48 (m, 21 1 ). 6.62 (m, 2H), 6.9 (s, i l l ). 7.2 (s, I I I ). 7.6 (s, 1H).
A7-(4-(4-(LH-imidazol-l-yl)
Figure imgf000045_0001
[00123] Reaction of 4-(4-(lH-imidazol-l-yl)butoxy)aniline (0.15 g, 0.64 mmol) and S'-(2- naphthylmethyl)-2-pyridyi thioimidate hydrobromide (0.34 g, 0.95 mrnol) in anhydrous acetonitrile (6 mL) and ethanol (20 mL) at room temperature afforded N-(4-(4-(lH-imidazol-l- yl)butoxy)phenyl)picolinimidamide (le) as a white crystal, yield: 0.0178 g, 0.053 mrnol, 9%; m.p. 99-101 °C. !H NMR (300 MHz, DMSO-de): δ 1.65 (m, 2H), 1.88 (m, 2H), 3.95 (t, J - 6.3, 2H), 4.04 (t, J - 7.0, 2H), 6.40 (br, 2H), 6.88 (m, 5H), 7.19 (s, 1H), 7.54 (m, 1 H), 7.64 (s, 1H), 7,93 (td, ./.· 7.7. 1.68. IH), 8,30 (d, ,/ 7.9. 1H), 8.62 (sd, ,/ 4.2. 1H) ppm; l3C NMR (300 MHz, CDCI3): δ 26.4, 28.1, 46.8, 67.4, 1 15,5, 118.7, 121.5, 122.6, 125, 1 , 129.5, 136.8, 137.1, 143.2, 147.8, 151.7, 153.0, 154.8 ppm.
Example 2B: Synthesis of meia-SvtbstitulM Phenoxyalkyl Linker Anti-Parasitic Compounds
[00124] FIG, 2B is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted meta to the arylimidamide group, e.g., Compounds lo-lq. Generally, reagents and conditions for synthesis of compounds according to FIG, 238 included: a) MOMCl, K2CO3, acetone, 30°C; b) RJ, K2C03, sealed tube, 80°C; c) HC1, MeOH/CH2Cl2, rt; d) 1,8- Dibromooctane, K2CG3, CFI3CN, reflux; e) imidazole, . >('() ;. CH3CN, reflux; I'} SnCl22H2Q, EtOAc, reflux; g) S-(2-naphthylmethyl)-2-pyridylthioimidate hydrobromide, CH3CN/EtOH (1 :3), rt.
Example 2C: Synthesis of orf/w-S bstit ted Phenoxyalkyl Linker Anti-Parasitic Compounds
[00125] FIG, 2C is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted ortho to the arylimidamide group, e.g., Compounds lr-lt. Generally, reagents and conditions for synthesis of compounds according to FIG, 2C included: a) RI, K2C03, sealed tube, 80°C; b) NaOH, DMSO, reflux; c) 1,8-Dibromooctane, K2C03, CH3CN, reflux; d) imidazole, K2C03, CH3CN, reflux; e) 8ηΟ2 '2Η20, EtOAc, ref!ux; f) S~(2~ naphih}'lmethyl)thioimidaie hydrobromide, CH3CN/EtOH, rt..
Example 2D: Synthesis of Pyrrole-Substituted Phenoxyalkyl Linker Anti-Parasitic
Compounds
[00126] FIG, 2D is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted with pyrrole, e.g., Compound In. Generally, reagents and conditions for synthesis of Compound lu according to FIG. 2D included: a) 1,8-dibromooctane, K2C03, acetone; b) pyrrole, K2C03, CH3CN; c) SnCl2.2H20, EtOAc; d) _?-(2-naph lmethyl)-2- pyridylthioimidate hydrobromide, CH3CN/EtOH (1 :3), rt.
Example 3A: Synthesis of Diphenylfuran Alkyloxy Linker Anti-Parasitic Compounds [00127] FIG. 3A is a synthetic scheme for various phenyl-unsubstituted diphenylfuran alkyloxy linker hybrid Compounds 2a~2g and 3a-g. Compounds 2a-e, 2g, 3a-e, and 3g were made according to FIG. 3A. Compound 2h was made according to FIG. 3A, but starting with 1- bromo-2-oxy(prop-2-yl)-4-nitrobenzene. Generally, reagents and conditions for synthesis of compounds according to FIG. 3A included: a) Pd(PPh )4, dioxane, 90°C; b) NBS, DMF, rt; c) K2C03, acetone, reflux; d) Pd(PPh3)4, K2C03, MeOH, toluene, 80°C; e) azole, NaH, DMF, rt; !') H2, Pd(C), EtOH-EtOAc; g) (i) 5-(2-naphthylmethyl-2-pyridylthioimidate hydrobromide, EtOH; (ii) NaOH; (iii) ethanolic HC1.
[00128] The synthesis of Compound 2c is representative, as follows.
2-(4-nitrophenyl)furan
Figure imgf000046_0001
[00129] Tetrakistriphenylphosphine palladium (0.5 mmol) was added to a stirred mixture of the 2-(tributylstannyl) furan (11 mmol) and 1 -bromo-4-nitrobenzene (10 mmol) in deaerated dioxane (25 mL) under a nitrogen atmosphere. The vigorously stirred mixture was heated at 90- 100 °C for 24 h. The solvent was evaporated under reduced pressure, the resulting solid was partitioned between ethyl acetate (200 mL) and 5 mL of concentrated ammonia to remove the palladium complex, washed with water, passed through celite to remove the catalyst, dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel, using hexanes/ethyi acetate (93/7, v/v) followed by recrystaliization from hexanes/ethyl acetate to afford a yellow solid, yield (68 %); rap. 134-135 °C, (Lit Molander et al. "Scope of the Suzuki-Miyaura Cross-Coupling Reactions of Potassium Heteroaryltrifiuoroborates," J. Org, Chem, 2009, 74(3), 973-980, the entire teachings of which are incorporated herein by reference), rn.p 131-132 °C; !! Ι NMR (DMSO-rf6) δ 6.71 (d, ,/ 3.6 Hz, i l l ). 7.02 (br s, ! H), 7,23 (d, J ------
3,6 Hz, 1 H), 7.90 (d, 8,8 Hz, 2H), 7.98 id. 8.8 Hz, 2H),
2~b romo-5-(4-nitrophenyl)fu ran
Figure imgf000047_0001
[00130] N-bromosuccinimide (2.13 gm, 12 mmol) was added portion-wise to a stirred solution of the previous nitro compound (10 mmol) in dimethylformamide (20 mL). The reaction mixture was stirred at room temperature for 12 h then poured onto cold water, the precipitate was collected and dried. Purification was conducted by column chromatography on silica gel, using hexanes/ethyl acetate (95/5, v/v). Yellow solid, yield 96 %; nip. 141-143 °C (see Ismail et al, "An efficient synthesis of 5,5'-diaryl-2,2'-bichalcophenes," Tel Lett 2006, 47(5), 795-797, the entire teachings of which are incorporated herein by reference); H NMR (DMSO-ifc) δ 6,83 (d, J = 3.6 Hz, IH), 7.35 (d, J = 3,6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 2H), 8.26 (d, J = 8,8 Hz, 2H); HRMS: m/z calculated for C10H7BrNO3: 267,9609, found: 267.9602 (M+ +1).
2-(4-(4-(bromobutosy)phenyI)-4,4,S,5-tetramethyl-l,3,2-dioxaborolane
Figure imgf000047_0002
[00131 ] 1,4-dibromobutane (36 mmol) was added to a solution of the p- hydroxyphenylboronic acid ester (1.32 gm, 6 mmol), dry K2CO3 (1.65 gm, 12 mmol) and CS2CO3 (0.39 gm, 1.2 mmol) in anhydrous dimethylacetamide (15 mL) under a nitrogen atmosphere. Stirring was continued for 12 h and ice water was added and the reaction mixture was filtered and air dried. Purification was performed by column chromatography on silica gel, using hexanes/ethyl acetate (93/7, v/v). White solid (73%) rn.p. 1 12-1 13 °C, lH NMR (DMSO-<¾) δ 1.27 (s, 12 H), 1.82-1.85 (m, 2 H), 1.94-1.98 (m, 2 H), 3.61 (t,■/ 5.2 Hz, 2 H), 4.01 (t, J ==5.2 Hz, 2 H), 6.93 (d, J --- 8.4 Hz, 2 H), 7.68 (d, J =8.4 Hz, 2 H).
2-(4-(4-(bromobutoxy)phenyl)-5-(4-nitrophenyl)furan
Figure imgf000048_0001
[00132] 2.3 mL deaerated 2 M aqueous solution of K2CO3 and 2-(4~
(bromobutox )phenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (2.73 mmol) in 5 mL deaerated methanol were added to a stirred solution of 2-bromo-5-(4-nitrophenyl)furan (2.28 mmol), and tetrakistriphenylphosphine palladium (0.1 14 mmol) in deaerated toluene (25 mL) under a nitrogen atmosphere. The vigorously stirred mixture was warmed to 80 °C for 24 h. The solvent was evaporated under reduced pressure. Purification was carried out by column chromatography on silica gel, using hexanes/ethyl acetate (90/10, v/v). Orange solid, yield (71 %); m.p. 81-83 °C; 1HNMR (DMSO-i ) δ 1.84-1.88 (m, 2 H), 1.97-2.00 (m, 2 H), 3.62 (t, J = 6.4 Hz, 2 H), 4.06 (t, J = 6,4 Hz, 2 H), 7.03-7.05 (m, 3 H), 7.40 (d, ./ 3.6 Hz, 1 H), 7.80 (d, J =8.4 Hz, 2H), 8.02 (it . I 8.8 Hz, 2H), 8.29 (d, J= 8.8 Hz, 2H).
l-(4-(4-(5-(4-nitropheiiyl)
Figure imgf000048_0002
[00133] 2-(4-(4-(bromobutox ')phenyl)-5-(4-nitrophenyl)furan (2 mmol) was added to a solution of the azole (2 mmol) and NaH (2.5 mmol) in dry DMF (10 ml.) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 h, then poured on ice- water (50 mL), filtered and dried. Purification was conducted by recrystallization from ethyl acetate/hexanes. Yellow solid, yield (71 %); m.p. 75-78 °C; !HNMR (DMSO~c 6) δ 1.66 (br s, 2H), 1.85 (br s, 2H), 4,02-4.05 (m, 4 H), 6.90 (br s, 1H), 7.01-7,04 (m, 3 H), 7.20 (br s, IH), 7.41 (d, J = 3.6 Hz, 1 H), 7.66 (br s, IH), 7.79 (d, J = 8.4 Hz, 2 H), 8.02 (d, J = 8.8 Hz, 2H), 8.27 (d, J ------ 8.4 Hz, 2H); FIRMS: m/z calculated for C23H22N3O4: 404.1610, found: 404.1595 (M+ +1).
4-(5-(4-(4-(lH-azol-l-yl)bu
Figure imgf000048_0003
[00134] Pd/C (10 %) (0.2 gm) was added to a de-aerated solution of l -(4-(4-(5-(4- nitrophenyl)furan-2-yl)phenoxy)butyl)~lH-imidazole (5 mmol) in ethyl acetate/ethanol (60 mL: 20 mL) mixture. Stirring in a Parr hydrogenator under 50 atmosphere until the uptake of hydrogen ceased, the consumption of hydrogen gave a clear solution. The solution was filtrated through celite, and the filtrate was removed under reduced pressure, the residue formed was used directly in the next step without further purification (the amine is easily oxidized and decomposes on standing). White solid, yield (94 %); m.p. 62-63 °C; "'HNMR (CDCi3) δ 1.80 (br s, 2 H), 202-204 (m, 2 H), 3.77 (s, 2 H), 4.00-4.06 (m, 4 H), 6.52 (d, J = 3.6 Hz, 1 H), 6.57 (d, J ----- 3.6 Hz, 1 H), 6.74 (d, ./ 8.4 Hz, 2 ! ! }. 6.91 (d, ./ 8.4 Hz, 2 ! ! }. 6.96 (br s, 1 H), 7.09 (br s, i l l ). 7.53 (br s, 1 1 1 ). 7.56 (d, J = 8.8 Hz, 2 H), 7,66 (d, ,/ 8, 8 Hz, 2 H); HRMS: m/z calculated for ( J l. N =().·: 374.1869, found: 374.1857 (M+ +1).
iV-(4-(5-(4-(4-(lH-imidazol-l-yl)butoxy)phenyl)furan-2-yl)phenyl)picolinimidami
hydrochloride
Figure imgf000049_0001
100135] £-(2-Naphthylmethyl)-2-pyridyl thioimidate hydrobromide ( 1.87 mmol) was added to a cooled solution of 4-(5-(4-(4-(lH-azol-l -yl)butoxy)phenyl)furan-2-yl)aniline (1.7 mmol) in dry ethanol (30 mL) in an ice bath. The reaction mixture was stirred at room temperature for overnight. After the disappearance of the starting material, the organic solvent was evaporated under reduced pressure to yield a crude oil product. Dr ' ether ( 100 mL) was added to the crude material and the mixture was stirred at room temperature for 1 h. The precipitate was filtered and washed with dry ether. The solid was dissolved in ethanol (2 mL); the solution was cooled to 0 °C in an ice bath and 1 0% NaOH was added until pH reached approximately 10. The free base was extracted with ethyl acetate (3 50 mL). The organic layer was washed with distilled water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting suspension was crystallized by adding dry hexanes and then filtered. The free base was suspended in dry ethanol (20 mL) and cooled to 0 °C in an ice bath. Freshly prepared ethanolic HCl solution (2 mL) was added to the suspension and the mixture was stirred at room temperature for overnight. The resulting red solution was concentrated under reduced pressure. The red crude solid was recrystaliized twice from dry ethanol and dry ether and filtered. Yellow solid, yield (57 %); m.p. 83-85 °C Dec ; 1HNMR (DMSO-<¾) δ 1.71 (t, J= 6 Hz, 2 H), 1.97-2 (m, 2 H), 4.06 (t, J = 6 Hz, 2 H), 4.30 (t, J = 6 Hz, 2 H), 6.98 i d. ./ 3.2 Hz, 1 H), 7.02 (d, ./ 8.8 Hz, 2 H), 7.19 (d, ./ 3.2 Hz, 1 H), 7.56 id. ./ 8.4 Hz, 2 H), 7.72 (br s, 2 H), 7.78 i d. ./ 8.4 Hz, 2 H), 7.86 (d,■/ 8,8 Hz, 2 H), 7,98 (d, ./ 8 Hz, 1 H), 8,21 -8.25 (ra, 1 H), 8, 51 (d, J = 7,6 Hz, 1 H), 8,91 (br s, 1 H), 9,26 (br s, 1H), 9.37 (s, 1H), 10. 15 (s, 1H), 11 .91 (s, I H); i3CNMR (DMSO-<¾) δ 24,9, 25.9, 47.7, 66.4, 106.2, 108, 8, 114.4, 1 19.3, 121.5, 122.4, 122.9, 123,6, 124.6, 124.8, 125.9, 128, 129.7, 132.6, 134,7, 137,8, 144, 150.5, 157.8, 158.9; HRMS: ni/z calculated for C29H28N5Q2: 478.2238, found: 478.2216 (base M+ +1); Anal. Calcd. For (' ,,! ! ·,->. {),. 2 HC1. 1.75 H20: C, 59.85; H, 5.63; N, 12.03; Found: C, 59.35; H, 5.77; N, 11.83.
Example 3B: Synthesis of Phenyl-Substituted Diphenylfuran Alkyloxy Linker Antiparasitic Compounds
[00136] FIG. 3B is a synthetic scheme for various phenyl substituted diphenylfuran alkyioxv linker hybrid compounds, each of which may be prepared, for example, from a suitably substituted aryl boronate according to FIG. 3A. Alternatively, compounds may be prepared from the corresponding phenol and bromoalkyi imidazole, as shown in FIG. 3B. The phenol may be prepared from a phenol protected aryl boronate according to FIG. 3A, followed by subsequent deprotection.
[00137] Compound 4j was made according to FIG. 33B. Generally, reagents and conditions for synthesis of compounds according to FIG. 3B included: a) Pd(PPh3)4, dioxane, 90°C; b) NBS, DMF, rt; c) K2C03, Cs2C03, DMA, rt; d) Pd(PPh3)4, K2C03, MeOH, toluene, 80°C; e) imidazole, NaH, DMF, rt; f) H2, Pd(C), EtOH-EtOAc; g) (1) ,S'-(2-naphthylmethyl)-2- pyndylthioimidate hydrobromide, EtOH; (ii) NaOH.
Example 3C∑ Synthesis of Phenyl-Suhstituted Diphenylfuran Alkyloxy Linker Anti- Parasitic Compounds
[00138] FIG. 3C is a synthetic scheme for various phenyl substituted diphenylfuran alkyloxy linker hybrid compounds. For example, Compounds 2h, 4k, 13b, and 13c were made according to FIG. 3C. Generally, reagents and conditions for synthesis of compounds according to FIG. 3C included: aa) Pd(PPh3)4, dioxane, 90°C; b) NBS, DMF, rt; c) K2C03, Cs2C03, DMA, rt; d) Pd(PPh3)4, K CO :. MeOH, toluene, 80°C; e) imidazole, NaH, DMF, rt; f) H2, Pd(C), EtOH-EtOAc; g) (i) -S,-(2-naphthylmethyl-2-pyridylthioimidate hydrobromide, EtOH; (ii) NaOH. Example 3D (Prophetic): Synthesis of Diphenylfuran Alkyloxy Linker Anti-Parasitic
Compounds
[00139] FIG. 3D is a prophetic synthetic scheme for various diphenylfuran alkyloxy linker hybrid Compounds 4a-i, each of which may be prepared, for example, from a suitably substituted aryl boronate according to FIG. 3A. Alternatively, Compounds 4a-i may be prepared from the corresponding phenol and bromoalkyi imidazole, as shown in FIG. 3D. The phenol may be prepared from a phenol protected aryl boronate according to FIG. 3A, followed by subsequent deprotection. Example 4 : Synthesis of Alkylamide Linker Anti-Parasitic Compounds
[00140] FIG, 4 is a synthetic scheme for various alkylamide linker hybrid Compounds
5a-f, 6a-f, and 7a-f. For example, precursor carboxylic acids were prepared similarly to FIG. 3A by a cross-coupling of a benzylaicohoi boronate ester with 2-(4-nitrophenyl)furan, nitro reduction, and imidamide formation. Oxidation of the benzyl alcohol provided the carboxylic acid compound shown in FIG. 4, and subsequent peptide coupling with the illustrated imidazoyl amine is proposed to afford Compounds 5a and 5c.
[00141 ] Similarly, for example. Compound 6a may be prepared from 2-(4- nitrophenyl)furan, followed by nitro reduction and imidamide formation. Bromination of the resulting furanyi compound followed by a metal -mediated carboxylation may provide the carboxylic acid shown in FIG. 4. Subsequent peptide coupling with the illustrated imidazoyl amine may afford Compound 6a. Similarly, for example, Compound 7a may be prepared from a suitable 4-aminobenzoic acid derivative. Imidamide formation may provide the carboxylic acid compound shown in FIG. 4, and subsequent peptide coupling with the illustrated imidazoyl amine may provide Compound 6a.
Example 5A (Prophetic): Synthesis of Phenylalkyl linker Anti-Parasitic Compounds
[00142] FIG. 5A is a prophetic synthetic scheme for various phenylalkyl linker hybrid
Compounds 8a and 8b. For example, Compound 8a and 8b may be prepared from phenyllithium and the corresponding dibromoalkane, as shown in FIG. 5A. Nitration of the resulting aikylaryl bromide followed by displacement of the bromide with imidazole can provide the nitrophenyl alkylimidazole. Subsequent reduction of the nitro group to the amine, followed by ami dine synthesis with naph1halene-2-ylmethylpyridine-2-carbimidothioate may provide Compounds 8a and 8b.
Example SB: Synthesis of Alkyl Linker Anti-Parasitic Compounds
[00143] FIG. SB is a synthetic scheme for various phenylalkyl linker hybrid
Compounds 9a-9d. The synthesis of Compound 9d is representative, as follows.
Benzyl (8-aminooctyl)carbamate
Figure imgf000051_0001
[00144] Benzyl chloroformate (1 g, 5.86 mmol) was added to 10 equivalents of 1 ,8- diaminooctane (8.45 g, 58.6 mmol) dissolved in 60 mL dry DCM/EtOH (1 : 1) in an ice bath. The mixture was allowed to stir for 3 hours at 0 °C and left to stir overnight at room temperature. The mixture was then filtered and partitioned between DCM (100 mL) and water (50 mL) and brine (50 mL) then dried over sodium sulfate. The solution was evaporated under reduced pressure and the crude product was purified by column chromatography using DCM/MeOH/TEA (100:6:0.7) as elueiit to obtain benzyl (8-aminooctyl)carbamate as a yellow oil, 0.95 g, yield 58%. Ί I NMR (300 MHz, CDC13) δ 1.31 -1.50 (m, 12 ! ! }. 2.68 U. ,/ 6.8 Hz, 2H), 3.16-3.22 (m, 2H), 4.78 (br s, 1 H), 5.10 (s, 2H), 7.31 -7.37 (m, 5H).
8-(lH-imidazol-l-yl)octan-l-amine
Figure imgf000052_0001
[00145] Aqueous glyoxal (40%, 0.88 mL, 6.19 mmol), ammonium acetate (0.48 g,
6.19 mmol), and aqueous formaldehyde solution (37% w/v, 0.51 mL, 6.19 mmol) were added to benzyl (8-aminooctyl)carbamate (0.87 g, 3.12 mmol) in methanol (8 mL). The reaction was heated to reflux overnight then the solution was evaporated under reduced pressure. The pH was rendered alkaline by the addition of 2N NaOH and the mixture was extracted with DCM (100 mL). The organic phase was dried over sodium sulfate and the liquid was evaporated under reduced pressure. The product was obtained after column chromatography purification over neutralized silica gel with DCM/MeOH (100: 1 ) as a brown oil of the protected aminoalkyl imidazole, 0.48 g. A dry 25 mL two-necked flask was charged with Pd/C (10%, 0.15 g) and the protected amine (0.48 g, 1.45 mmol) in 20 mL absolute ethanoi under nitrogen. The mixture was stirred under 1 atmosphere of hydrogen for 24 hours. The mixture was filtered and ethanoi was removed under reduced pressure to obtain the crude product which was purified by column chromatography over silica gel with DCM/MeOH/TEA (100: 15 :0.1 ) to obtain 8-(lH-imidazol-l- yl)octan-l -amine as a yellow oil, 0.15 g, overall yield 25% from benzyl (8- aminooctyl)carbamate. ¾ NMR (300 MHz, CDC13) δ 1.31 (br s, 8H), 1.42- 1 .46 (m, 2H), 1 .76- 1 .85 ( ns. 4H), 2.69 (t, J ------ 6.7 Hz, 2H), 3,93 (t, J ------ 7 Hz, 2H), 6.91 ( I . ,/ 1.1 Hz, 1 1 1 ). 7.06 (br t,
./ 0.9 Hz, i l l ). 7,47 (s, i l l ).
N-(8-(lH-imidazol-l-yl)oc
Figure imgf000052_0002
[00146] S-(2-Naphthylmemyl)-2-pyridyl thioimidate hydrobromide (0.40 g, 1.1 1 mmol) was added to a cooled solution of 8-(lH-imidazol-l -yl)octan-l -amine (0.1 g, 0.51 mmol) in dry ethanoi :acetonitrile (7:3) (10 mL) in an ice bath. The reaction mixture was stirred at room temperature for 48 hours. After the disappearance of the starting material, the organic solvent was evaporated under reduced pressure to yield a crude oil. Dry ether (50 mL) was added to the crude raaterial and the mixture was stirred at room temperature overnight. The precipitate was filtered and washed with dry ether. The solid was dissolved in ethanol (2 mL); the solution was cooled to 0 °C in an ice bath and 10% NaOH was added until the pH reached approximately 10. The free base was extracted with ethyl acetate (3 χ 25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting suspension was purified by column chromatography over silica gel using DCM/MeOH/TEA (9.5: 1.2:0.6) as eluent then further purified by 5 mL hexanes/di ethyl ether (1 : 1) to yield a buff powder, 0,085 g, 55%. H NMR (400 MHz, CDCI3) δ 1 .28-1.45 (m, 8H), 1.67-1.82 (ra, 4H), 3,29 ( l. J 6.9 Hz, 2H), 3.93 (t, ./ 7 Hz, 2H), 6.04 (br s, 2H), 6.91 (t, J ------- 1.2 Hz, i l l ). 7,06 (t, J
= i Hz, 1H), 7.36 (ddd, J, = 7.6 Hz, J2 = 4.8 Hz, J3 = 1.2 Hz, 1 1 1 ). 7,48 (br s, i l l ). 7.79 (id, Js = 7.8 Hz, ./· = 1.7, 1H), 8.23 (d, ./ 7.8, 1H) 8.55 (ddd, J, = 4.8 Hz, ./ · = 1.7 Hz, ./, = 0.95 Hz, I I I ). i C NMR (100 MHz, CDCI3) δ 26.48, 27.19, 28.97, 29.1 7, 29.44, 31.04, 42.55, 47.00, 118.74, 120.83, 124.85, 129.40, 136.89, 137.06, 147.82, 151.49. HRMS: 300.21707 | M M ' j.
Example 6.4: Synthesis of Unsubstituted and Certain Substituted Biphenyl Linker Anti- Parasitic Compounds
[00147] FIG. 6A is a synthetic scheme for various unsubstituted and substituted biphenyl linker anti-parasitic compounds, which was used to produce Compounds 19a, lOd, 19e, lOh, 10k, and 101. Biphenyl linkers in these compounds were either unsubstituted or were substituted meia to the amidine group. Generally, reagents and conditions for synthesis of compounds according to FIG. 6A included: dibromoaikane, K2CO3, CH3CN, reflux; b) imidazole, K2C03, CH3CN, reflux; c) 2-aikoxy-4-nitroiodobenzene, Pd(dppf)Cl2, K2CO3, DMSO, 100°C; d) SnCl2.2H20, EtOAc, reflux; e) 5-(2-naphthylm.ethyl)-2-pyndylthioimidate hydrobromide, CH3CN/EtOH (1 :3), rt.
Synthesis of 2-( 4-( 4-bromohutoxy)phenyl)-4, 4, 5, 5-tetmmethyl- 1, 3, 2-dioxaborolane.
[00148] Reaction of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (2.00 g, 9.1 mmol), 1,4-dibromobutane (5.42 mL, 9.80 g, 45.4 mmol), and potassium carbonate (2.5 g, 18.2 mmol) was performed in dry acetonitrile under reflux overnight followed by filtration and evaporation of the filtrate under reduced pressure. Purification of the crude product was performed by column chromatography on silica gel using hexane to hexane/ethyl acetate (10: 1) to afford a white solid which was further ciystallized from methanol to yield the product as a white crystalline solid. Yield 2.42 g (75%), mp = 62-64 °C, lit mp 64-66 "C.1 The lH NMR spectrum of this material was consistent with the literature report.
Figure imgf000054_0001
Synthesis of l-(4-(4-(4,4 ,5-tetramethyl-l,3,2^iomborolan-2-yl)p noxy)bu
[00149] Reaction of 2-(4-(4-bromobutoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (1.38 g, 3.9 mmol), imidazole (0.52 g, 7.8 mmol), and potassium carbonate (1.07 g, 7.8 mmol) was performed in dry acetomtrile under reflux overnight followed by filtration and evaporation of the filtrate under reduced pressure. Purification of the crude product was performed by column chromatography on silica gel using DCM; MeOH (25: 1) to afford a white solid which was further crystallized from the ethyl acetate/hexane to yield the product as white crystalline solid. Yield 0.75 g (56%), mp=113-115 °C. "!H NMR (400 MHz, CD(¾) 61.35 (s, 12H), 1.78-1.83 (m, .21 i s. 1.97-2.04 (m, 2H), 4.00-4.06 (m, 4H), 6.88 (d, ./ 6.8 Hz, 2H), 6.95 (s, i l l ). 7.09 (s, i l l ). 7.51 (s, i l l ). 7.76 (d, ./ 6.8 Hz, 2H).
Figure imgf000054_0002
Synthesis of l-(4-((4'-nitro-[ 1, 1 '-biphenyl]-4-yl)oxy)butyl)-lH-imidazole.
[00150] l-(4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)butyl)-lH- imidazole (0.35 g, 1.02 mmol), 4-iodonitrobenzene (0.35 g, 1.4 mmol), and tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.05 mmol) were added to a three necked flask. Degassed dry DMF (10 ml) was added and the flask was purged with nitrogen. Degassed potassium carbonate (1 mL of a 2M aqueous solution) was added and the flask was heated to reflux overnight. The reaction mixture was filtered over celite, then the filtrate was evaporated under reduced pressure and purified by column chromatography on silica gel using hexanes/ethyl acetate (1 :3) as the eluent to afford the pure product as a yellow powder, yield 0.25 g (73%), mp= 1 13-115 °C. ¾ NMR (400 MHz, CDC13) 51 ,82-1.88 (m, 2H), 2,01 -2.08 (m, 2H), 4.03-4.09 i ns. 4H), 6,97-7.0 ! (m, 3H), 7.10 (s, i l l ). 7.53-7,60 (ra, 3H), 7,70 id. ,/ 8.8 Hz, 2H), 8,28 id.
Figure imgf000054_0003
Synthesis of 4'-(4-(lH-imida∑ol-l-yl)butoxy)-fl, 1 '-biphenylJ-4-amine.
[00151 ] A mixture of l -(4-((4'-nitro-[l,r-biphenyl]-4-yl)oxy)but d)-lH-imidazole
(0.23 g, 0.68 mmol) and tin chloride dihydrate (0.77 g, 3.40 mmol) in ethyl acetate was heated at reflux overnight. The reaction mixture was cooled, then aqueous sodium hydroxide (2N) was added until the pH reached 1 . The product was then extracted with ethyl acetate (25 ml, χ 3), dried over anhydrous sodium sulfate, filtered over celite, and evaporated under reduced pressure to yield the product as a buff powder which was taken directly to the next step without further purification, yield 0.19 g (91 %). AH NMR (300 MHz, CDC13) δ 1.76-1.85 (ra, 2H), 1.97-2.07 (ra, 2H), 3.68 (br s, 2H), 3.99-4,07 (m, 4H), 6,74-6.77 (ra, 2H), 6.91-6.95 (m, 3H), 7.09 (s, IH), 7.35-7.38 (m, 2H), 7.45-
Figure imgf000055_0001
Synthesis of N-(4'-(4-(lH-imidazol-l-yl)butoxy)-[ 1, 1 '-biphenyl]-4-yl)picolinimidamide.
[00152] 5'-(2-Naphthy imethyl)-2-pyidy3 thioimidate hydrobromide (0.40 g, 1.1 mmol) was added to a cooled solution of 4'-(4-(l H-imidazo]-l-yl)butox ')-[l-,l'-biphenyl]-4-arnine (0. 15 g, 0.48 mmol) in dry ethanol: acetonitrile (7:3, 10 mL) in an ice bath. The reaction mixture was stirred at room temperature for 48 hours. After the disappearance of the starting material, the organic solvent was evaporated under reduced pressure to yield the product as an oil. Dry diethyl ether (100 mL) was added to the crude material and the mixture was stirred at room temperature overnight. The precipitate was filtered and washed with dry diethyl ether. The solid was dissolved in ethanol (2 mL), then the solution was cooled to 0 °C in an ice bath and 10% NaOH was added until pH reached approximately 10. The free base was extracted with ethyl acetate (3 χ 25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting suspension was purified by column chromatography over silica gel (neutralized by washing with tri methyl amine) using DCM:MeOH (200: 1 to 50: 1) as eluent then further purified by crystallization from hexanes/ethyl acetate to yield yellow crystals, 0.135 g (68%). ]H NMR (300 MHz, CDC13) 6 1.80-1.87 (m, 2H), 1.99-2.06 (m, 2H), 4.02-4.09 (m, 4H), 5.91 (brs, 2H), 6.95-6.98 (m, 3H), 7.08-7.10 (m, 3H), 7.42 (ddd, J ! . ! Hz, ./ · 4.9 Hz, . 6.8 Hz, 1H), 7.53-7.60 (m, 5H), 7.84 (td, ./.· 1 .7 Hz, ./■ 7.7 Hz, 1H), 8.46 i d. ./ 7.7 Hz, i l l ). 8,59-8.61 (m, I I I ).
Example 6B: Synthesis of Certain Substituted Biphenyl linker Anti-Parasitic Compounds
[00153] FIG. 63B is a synthetic scheme for various substituted biphenyl linker antiparasitic compounds, which was used to produce Compounds 10b, 10c, lOi, and lOj. Biphenyl linkers in these compounds were substituted or (ho to the amidine group. Generally, reagents and conditions for synthesis of compounds according to FIG. 6B included: a) dibromoalkane, K2CO3, CH3CN, reflux; b) imidazole, 2C03, CH3CN, reflux; c) 23a,b, Pd|;P(Ph)3]4, K2C03, DMF, 100°C; d) SnCl2.2H20, EtOAc, reflux; e) 5-(2-naphthylmeihyl)-2-pyndylihioimidate hydrobromide, CH3CN/EtOH (1 :3), rt.
Example 6C: Synthesis of Certain Substituted Biphenyl Linker Anti-Parasitic Compounds [00154] FIG. 6C is a synthetic scheme for various substituted biphenyl linker antiparasitic compounds, which was used to produce Compounds lOf and 10m. Biphenyl linkers in these compounds were substituted meta to the aikoxy linking group. Generally, reagents and conditions for synthesis of compounds according to FIG. 6C included: a) TsCl, K2C03, acetone, reflux; b) Mel, K2C03, sealed tube, CH3CN, reflux; c) bis(pinocolato)diboron, Pd(dppf)Cl2, AcOK; d) 4-nitro-iodobenzene, Pd(dppf)Cl2, dimethoxyethane/DMF/water (7:3: 1), reflux; e) aq NaOH, EtOH/DMSO; f) 1,4-dibromo butane or 1,6-dibromohexane, K2C03, CH3CN, reflux; g) imidazole, K2CO3, CH3CN, reflux; h) SnCl2.2H20, EtOAc, reflux; i) 5-(2-naphthy1methyl)-2- pyridylthioimidate hydrobromide, CH3CN/EtOH (1 :3), rt.
Example 6D: Synthesis of Certain Substituted Biphenyl Linker Anti-Parasitic Compounds [ 00155] FIG. 6D is a synthetic scheme for various substituted biphenyl linker antiparasitic compounds, which was used to produce Compounds lOg and 10η. Biphenyl linkers in these compounds were substituted ortho to the aikoxy linking group. Generally, reagents and conditions for synthesis of compounds according to FIG. 6D included: a) TsCl, acetonitrile, 2CO3, reflux ; b) Bis(pinacolato)diboron, Pd(dppf)Cl2, AcOK, dioxane, 100°C; c) l-Iodo-4- nitrobenzene, Pd[P(Ph)3]4 or Pd(dppf)Cl2, K2C03, DME:DMF:H20 (7:3: 1 ),100°C; d) aq NaOH, EtOH/DMSO; e) dibromoalkane, acetonitrile, K2C03, reflux; f) Imidazole, K CO ;, reflux; g) SnCl2.2H20, ethyl acetate, reflux; h) 5,-(2-naphthylmethyl)-2-pyridylthioimidate hydrobromide, ( ! ! .( \ i JO! ! i ! :3 ). rt.
Example 7A: Synthesis of Phenyl-Piperazinyl-Phenyl Linker Anti-Parasitic Compounds [00156] FIG. 7A is a synthetic scheme for various phenyl-piperazinyl-phenyl linker anti-parasitic compounds, which was used to produce Compounds lla-lld. Generally, reagents and conditions for synthesis of compounds according to FIG. 7A included: a) NMP, DIPEA, 4- chloronitrobenzene; b) α,ω-dihaloalkane, K2C0 , acetone or Cs2C0 , DMF; c) imidazole or 1 ,2,4-triazole, Cs2C03, DMF; d) Pd/C, H2, EtOAc/MeOH; e) ,S-(2-naphthylmethyI-2- pyridylthioimidate hydrobromide, CH3CN/EtOH.
Example 7B: Synthesis of Phenyl-Piperazinyl Linker Ants-Parasitic Compounds
[00157] FIG. 7B is a synthetic scheme for various phenyi-piperazinyl linker antiparasitic compounds, e.g., corresponding to Structural Formula (XVII). Generally, reagents and conditions for synthesis of compounds according to FIG. 7B included: a) K2C03/DMSO; b) α,ω-dihaloalkane, e.g., 1,6-dibromohexane, Cs2C03, DMF; c) imidazole, Cs2C03, DMF; d) Pd/C, H2, MeOH; e) 5-(2-naph1hylmethyl-2-pyridylthioimidate hvdrobromide, CH^CN/EiOH. The synthesis of Compound 12a, N-(4-(4-(6-(lH-imidazol-l -yl)hexyl)piperazin-l- yl)phenyl)picolinimidamide, is representative, as follows.
Step 1: Synthesis of l-(4-nitrophenyl)piperazine
Figure imgf000057_0001
00158 4-Chloro nitrobenzene (1.57 g, 10 mmol, 1 eq), piperazine (1.12 g, 13 mmol,
1.3 eq), potassium carbonate (2.07 g, 15 mmol, 1.5 eq) and tetra-N-butyl ammonium iodide (37 mg, 0.1 mmol, 0.01 eq) were added to a reaction vessel, then dimethyl sulfoxide (25 mL) was added under an inert atmosphere. The resulting suspension was heated at 120 °C overnight. The reaction mixture was cooled, diluted with ice water (40 mL), neutralized with 2N hydrochloric acid and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na2S04, and concentrated under reduced pressure to yield l-(4-nitrophenyl)piperazine as a yellow solid. Yield = 1.65 g, 80%; *H N.V1R (CDC13, 500 MHz) δ 3.01-3.03 (t, 4H, ./ 5.15 Hz), 3.37-3.39 (t, 4H, 4.9 Hz), 6.81-6.82 (d, 2H, J ------ 9.3 Hz),
8, 1 1 -8.13 (d, 2H, .7 = 9.35 Hz).
Step 2: Synthesis of l-(6-bromohexyl)-4-(4-nitrophenyl)piperazine
Figure imgf000057_0002
00 59 1 -(4-nitrophenyl)piperazine (1.03 g, 5 mmol, 1 eq), cesium carbonate (25 mmol, 8.14 g, 5 eq) were added to dry dimethylformamide (25 ml.) under an inert atmosphere. To the resulting suspension was added 1,6-dibromohexane (1.02 mL, 6.6 mmol, 1.3 eq) and the mixture was stirred at room temperature for 24 hours. On completion, the reaction mixture was extracted with ethyl acetate (25 mL x 2). The combined organic layers were evaporated under reduced pressure and the resulting liquid was purified by column chromatography using ethyl acetate hexane (1 : 1 ) as an eluent. Fractions containing the main product were combined and evaporated to dryness to give I -(6-bromohexyl)-4-(4-nUrophenyl)piperazine as a yellow solid. Yield = 550 mg, 30%; j i i NMR (CDC13, 500 MHz) δ 1.37-1.42 (m, 2H), 1.47-1.59 (m, 4H), 1.87-1.93 (m, 2H), 2.40-2.43 (t, 2H, J= 7.45 Hz), 2.59-2.61 (t, 4H, J ------ 5.2 Hz), 3.43-3.46 (m,
6H), 6.83-6.86 (d, 2H, ./ 9.4 Hz), 8, 13-8.15 (d, 21 1. 9.4 Hz).
Step 3: Synthesis of I-(6-( lH-imid zol-i-yl)hex >l)~4~(4~nitrophenyl)piperazi
Figure imgf000058_0001
[00160] l-(6-bromohexyl)-4-(4-nitrophenyl)piperazine (518 mg, 1.4 mmoi, 1 eq), 1H- imidazole (143 mg, 2.1 mmoi, 1.5 eq) and cesium carbonate (2.28 g, 7 mmol, 5 eq) were added to a reaction vessel, then dry dimethylformamide (10 ml.) was added. The reaction was stirred at 50 °C for 6 hours, then the reaction mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure and purified by column chromatography using dichloromethane/methanol (95:5) as an eluent. Fractions containing the product were combined and evaporated to dryness to give 1-(6-(1Η- imidazol-l-yl)hexyl)-4-(4-nitrophenyl)piperazine as a brown solid. Yield :=: 365 mg, 73%; Ή NMR {(1X 1 ,. 500 MHZ) δ 1.31-1 ,37 (m, 4H), 1 ,48-1.54 (m, 2! I ). 1.76-1.82 (m, 21 1 ). 2.34-2,37 (t, 2H, J = 7.4 Hz), 2.55-2.57 (t, 4H, J = 5,0 Hz), 3,41-3,43 (t, 4H, J = 4.9 Hz), 3.92-3.95(1, 2H, J = 7.0 Hz), 6.80-6.82 (d, 2H, J = 9.3 Hz), 6.9 (s, 1H), 7.05 (s, 11 1 ). 7.46 (s, 1H), 8.10-8.12 (d, 2H, J : = 9.25 Hz),
Step 4: 4-(4-(6-(lH-imidaz -]-y4)hexy!)piperazin-l-y!) iline
Figure imgf000058_0002
[00161] l-(6-(lH-imidazol-l -yl)hexyl)-4-(4-ratrophenyl)piperazme (322 mg, 0,9 mmol) was dissolved in methanol (30 mL). This mixture was hydrogenated at 40-45 psi using 10% Pd/C as catalyst for 30 minutes in a Parr hydrogenator. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated to give 4-(4-(6-(lH-imidazol-l- yl)hexyl)piperazin-l-yl)aniline as a brown solid. Yield = 275 mg, 93%; 5H NMR (DMSO-o'6, 500 MHz) δ 1.18-1.24 (m, 2H), 1.26-1.32 (m, 2H), 1.39-1.43 (m, 2H), 1.67-1.73 (m, 2H), 2.25- 2.27 (t, 2H, ./ 7.2 Hz), 2.44 (s, 4H), 2.88 (s, 4H), 3.92-3.95 (t, 2H, J ------ 7.0 Hz), 4.53 (s, 2H),
6,47-6.49 (d, 2! i. ./ 8.55 Hz), 6.66-6.68 (d, 2H, J ------- 8.65 Hz), 6.87 (s, i l l ). 7.15 (s, 1H), 7.6 (s,
1H).
Step 5: Synthesis of -(4-(4-(6-(lH4midazol-l-yl)hexyl)piperazin-l-yl)phenyl) picolinimidamide
Figure imgf000058_0003
[00.162] £-(2-Naphthylme&yl)-2-pyridyl thioimidate hydrobromide (216 mg, 6 mmol,
1 .2 eq) was added to an ice cooled solution of 4-(4-(6-(lH-imidazol-l-yl)hexyl)piperazin-'J - yl)aniiine (164 mg, 0.5 mmol, 1 eq) in a mixture of absolute ethanol/acetonitrile (2: 1 , 15mL). The resulting mixture was stirred at room temperature for 24 hours. Upon completion of the reaction indicated by TLC, the solvent was evaporated under reduced pressure. To the crude residue was then added dry diethyl ether (50 mL) and the resultmg suspension was stirred at room temperature for 6 hours. The separated solid was filtered and washed with dry diethyl ether. The solid was suspended in cold ethanol (5 mL); the mixture was placed in an ice bath and 10% NaOH was added until a pH of approximately 10 was reached. The free base was extracted with ethyl acetate (3 * 20 mL). The organic layer was washed with distilled water, dried over anhydrous K2C03, filtered and concentrated under reduced pressure. Dry hexane was added to the resulting suspension, which was then filtered to provide the product as the free base (light yellow solid). Yield = 108 mg, 50%; !H NMR (DMSG-a6, 500 MHZ) δ 1.20-1.26 (m, 2H), 1.28-1.34 (m, 2H), 1.41 -1.46 (m, 211), 1.68-1.74 (m, 2H), 2.27-2,30 (t, 2H,■/ 7.2 Hz), 2.49 (s, 4H), 3.07 (s, il l ). 3.93-3 ,96 (t, 21 1. J ------ 7. 1 Hz), 6.36-6,66 (br, 2H), 6.83-6.84 (d, 2H, 8.7
Hz), 6.88 (s, 1H), 6.92-6.94 (d, 2H, J = 8.8 Hz), 7.16 (s, IH), 7.52-7.54 (dd, IH, J = 5,5, 7.1 Hz), 7.61 (s, IH), 7.91-7.94 (td, ! ! !. ./ 1.6, 7.8 Hz), 8.29-8.30 (d, IH, J = 7.9 Hz), 8.61-8.62 (d, IH, ■/ 4.5 Hz); 1 C NMR i DMSC)-. /,. 125 MHz) δ 26.32, 26.63, 26.87, 31.01 , 46.35, 49.49, 53.40, 58.25, 1 1 7.10, 119.70, 121 .57, 122.60, 125.66, 128.74, 1 37.48, 137.66, 142.34, 147. 15, 148.41, 151.94, 152.23; HRMS exact mass of (M+H)+, 432.2876 amu; observed mass of (M+H)+, 432.2878 amu.
Example 8: Biological Evaluation of Anti-Parasitic Compounds
[00163] Selected compounds were tested to determine ICso values in an intracellular amastigote assay (L. donovani) as follows. Peritoneal macrophages were obtained from CD-I mice, plated at a density of 105 cells/well in 96- well plates in macrophage medium (RPMI 1640 with Glutamax (Life Technologies, pH=7.4 containing 100 ^ig/mL streptomycin, 100 U/mL penicillin, and 10% heat-inactivated fetal bovine serum), and permitted to adhere overnight. Macrophages were then infected with L. donovani LV82 strain promastigotes at a ratio of five parasites per macrophage. After overnight incubation at 37°C in a humidified atmosphere containing 5% C02, samples were washed with Hank's Balanced Salt Solution (HBSS), then compounds or the standard drag amphotericin B were added in two-fold serial dilutions in macrophage medium at a final volume of 200 ^iL/well. Plates were then incubated for three days under the conditions described previously. After incubation, medium was removed and cells were washed with HBSS. Fixation of the cells was then performed using 10% formalin for 30 rain. Cells were then permeabilized with 0.1% Triton in PBS, washed with PBS, and stained with 1 |ig/mL DAPI for 10 min. Plates were then read using an Array Scan XTI High Content Platform imaging system (Life Technologies) to quantitate macrophage nuclei and parasite nuclei. The data obtained was used to determine the number of parasites per macrophage in each well . A four-parameter curve function available in KaleidaGraph software was then employed to calculate IC50 values.
[00164] Selected compounds were tested to determine IC50 values in an intracellular amastigote assay (L. donovani) and CC50 values against J774 macrophages, and selectivity was calculated as CC50/IC50 as follows. The cytotoxicity of the compounds on J774 macrophages was evaluated as outlined by Zhu et al. See Zhu, et al, Bioorg. Med. Chern. (2015) 23: 5182- 5189, the entirety of which is incorporated herein by reference. J774 macrophages were maintained in R MI + GlutaMAX medium (Gibco) supplemented with 100 U/mL penicillin, 100 μ§/πΛ, streptomycin, and 10% fetal bovine serum at 37°C in a humidified 5% CO? atmosphere. Macrophages were plated at a density of 5 χ 103 cells/well in the presence or absence of serial dilutions of test compounds, vehicle, or podophyllotoxin standard drug in a final volume of 100 uL. After 72 hour incubation under the same conditions described above, 25 μί of a 5 mg/mL solution of 3-(4,5-dimethylthiazoI-2-yi)-2,5-diphenyltetrazoIium bromide (MTT) in water was added to each well, and the plate was returned to the incubator for 2 hr. A solution of 10% SDS (w/v) in 50% aqueous dimethylformamide was then added to each well, then the plate was incubated for an additional 3-5 h at 37°C. Optical densities for each well were then read at 570 nra using a SpectraMax Plus microplate reader and CC50 values were determined as mentioned in the protocol for the intracellular /,, amazonensis assay.
[00165] The above procedures for J774 macrophages were used with slight modification for HepG2 hepatocellular carcinoma cells. HepG2 cells (5 10~' in 100 μί) were incubated for 72 h with serial dilutions of compounds in DMEM medium supplemented with 1 0% fetal bovine serum and antibiotics. MTT was added and absorbance at 570 nm provided an assessment of cell proliferation versus compound concentration, from which CCso against HepG2 was determined in μΜ. See Werbovetz, K., et al. Int. J. Toxicol 2014, 33, 282-287, the entirety of which is incorporated herein by reference.
Example 8A: Biological Evaluation of Phenoxyalkyl Linker Compounds Against L. Donovani, CC50 values against J774 macrophages, and CC50 values against HepG2 [00166] FIG. 8A is a table demonstrating IC50 values in μΜ against intracellular L. donovani, CC50 values against J774 macrophages, and CC50 values against HepG2 for various phenoxyalkyl linker compounds compared to amphotericin B, podophyllotoxm, and doxorubicin. Example 8B: Biological Evaluation of Diphenylfuran Alkyloxy Linker Compounds
[00167] FIG. 8B is a table demonstrating IC50 values in μΜ against intracellular L. donovani, and CC50 values against J774 macrophages, and HepG2 for various diphenylfuran linker compounds compared to amphotericin B, podophyllotoxm, and doxorubicin.
Example 8Cs Biological Evaluation of Biphenyl Alkyloxy Linker Compounds Against L. Donovani, CC50 values against J774 macrophages, and CC50 values against HepG2
[00168] FIG. 8C is a table demonstrating IC50 values in μΜ against intracellular L. donovani, CC50 values against J774 macrophages, and CC50 values against HepG2 for various biphenyl linker compounds compared to amphotericin B, podophyllotoxm, and doxorubicin. Example 8F: Biological Evaluation of Phenyl-Piperazinyl-Phenyl Alkyloxy Linker Compounds Against L. donovani, and CC50 values against J774 macrophages
[00169] FIG. 8D is a table demonstrating IC50 values in μΜ against intracellular L. donovani and CC50 values against J774 macrophages for various phenyl-piperazinyl-phenyl linker compounds compared to amphotericin B and podophyllotoxm.
DEFINITIONS
[00170] As used herein, an "alkyl" group includes straight chain and branched chain alkyl groups having a number of carbon atoms, for example, from 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4. Examples of straight chain alkyl groups include groups such as methyl, ethyl, n- propyl, Λ-butyl, n-pentyl, n-hexyl, Λ-heptyl, and n-octyl groups. Examples of branched alkyl groups include, e.g., isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above and include, without limitation, haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alk laminoalkyl, dialkyiaminoalkyl, alkoxyalkyl, or carboxyalkyl.
[00171 ] As used herein, an "alkoxy" group means a hydroxy 1 group (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group. Examples of linear alkoxy groups include, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy. Examples of branched alkoxy groups include, e.g., isopropoxy, seobutoxy, tert-butoxy, isopentoxy, or isohexoxy. Examples of cycloalkoxy groups include, e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy. Representative substituted alkoxy groups may be substituted one or more times. [00172] As used herein, a '"cycloaikyi" group includes mono-, hi- or tricyclic alkyl groups having from 3 to 12 carbon atoms in each ring, for example, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. Exemplar}' monocyclic cycloaikyi groups include, for example, cvclopropvl, cyclobutyl, cyclopentyl, cyciohexyi, cycloheptyl, cyclooctyl, and the like. A cycloaikyi group may have a number of ring carbons of from 3 to 8, 3 to 7, 3 to 6, or 3 to 5. Bi- and tricyclic ring systems may include both bridged cycloaikyi groups and fused rings, e.g., bicyclo[2.1.1]hexane, adamantyl, decaiinyl, and the like. Substituted cycloaikyi groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. Substituted cycloaikyi groups may include rings that may be substituted with straight or branched chain alkyl groups. Representative substituted cycloaikyi groups may be mono-substituted or substituted more than once, for example, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyciohexyi groups.
[001731 As used herein, a "heterocycloalkyl" ring means an aromatic carbocyclic ring having one or more ring carbon atoms replaced by a heteroatom (e.g., N, S, or O). Non-aromatic heterocy clic rings may have 4, 5, 6, 7, or 8 ring atoms. Examples include oxazolinyl, thiazolinyl, oxazolidinyl, thiazoiidinyl, tetrahydrofuranyl, tetrahyrothiophenyl, morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl, thiazoiidinyl, and the like.
[00174] As used herein, an "'aryF" group means a carbocyclic aromatic hydrocarbon.
Aryi groups herein include monocyclic, bi cyclic and tricyclic ring systems. Aryi groups include, e.g., phenyl, azulenyl, heptalenyl, biphenyl, ffuorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, naphthyl, and the like, for example, phenyl, biphenyl, and naphthyl. Aryi groups may contain, for example, 6 to 14, 6 to 12, or 6 to 10 ring carbons. In some embodiments, the aryi groups may be phenyl or naphthyl. Although the phrase "aryi groups" may include groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl or tetrahydronaphthyl), an "aryi" group, unless stated to be substituted or optionally substituted, does not include aryi groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl may be referred to as substituted aryi groups. Representative substituted aryi groups may be mono-substituted or substituted more than once. For example, monosubstituted aryi groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl, which may be substituted with substituents such as those above.
[00175] As used herein, an "aralkyl" group means an alkyl group in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryi group. In some embodiments, aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. Substituted aralkyl groups may be substituted at the alkyl, the aryi or both the alkyl and aryl portions of the group. Representative aralkyl groups include, e.g., benzyl and phenethyi groups and fused (cycloalkylaryl)alkyl groups such as 4-indanylethyl. Substituted araikyis may be substituted one or more times.
[00176] As used herein, a "heteroaryl" group means a carbocyclic aromatic ring having one or more ring carbon atoms replaced by a heteroatom (e.g., N, S, or O). Heteroaryl groups may include, for example, imidazolyl, isoimidazolyi, thienyi, furanyi, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrrolyl, pyrazmyl, thiazoyl, isothiazolyl, oxazolyl, isooxazoiyl, 1,2,3- trizaolyl, 1 ,2,4-triazolyl, and tetrazoiyl. Heteroaryl groups also include fused poly cyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples of heteroaryl groups may include benzothienyi, benzofuranyl, indolyl, qumolinyl, benzothiazolyl, benzoisothiazolyi, benzooxazolyl, benzoisooxazolyl, benzimidazolyi, quinolinyl, isoquinolinyl and isoindolyl.
[00177] Groups described herein having two or more points of attachment (e.g., divalent, trivalent, or polyvalent) within the compound of the technology may be designated by use of the suffix, "ene." For example, divalent alkyl groups may be alkylene groups, divalent aryl groups may be arylene groups, divalent heteroaryl groups may be heteroarylene groups, and so forth. In particular, certain polymers may be described by use of the suffix "ene"' in conjunction with a term describing the polymer repeat unit.
[00178] As used herein, "optionally substituted" means a compound or group that may be substituted or unsubstituted. The term "substituted" refers to an organic group (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein may be replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom may be replaced by one or more bonds, including double or triple bonds, to a heteroatom. A substituted group may be substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group may be substituted with 1 , 2, 3, 4, 5, or 6 substituents.
[00179] Examples of substituent groups include: halogens (F, CI, Br, and I); hydroxy!: alkoxy, alkenoxy, aryioxy, aralkyloxy, heterocyclooxy, and heterocycloalkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxy amines; aralkoxy amines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; or nitnles. A "per"- substi luted compound or group is a compound or group having all or substantially all substitutable positions substituted with the indicated substituent. For example, 1,6-diiodo peril uoro hexane indicates a compound of formula C6F12I2, where all the substitutable hydrogens have been replaced with fluorine atoms.
[00180] In particular, suitable substituents for an aikyl group, cycioalkyl group, heterocycioalkyl group, or an aryl group ring carbon are those which do not substantially interfere with the activity of the disclosed compounds. Examples include -OH, halogen (-Br, -, - I and -F )- -OR \ -0(CO)RA, -(CQ)RA, -CN, -N02, -CO?H, -S03H, -N3¾, -NHRA, -N(RARB), - (C())ORA, -{ CO )! !. -COM ! -, -CONHRA, -CON(RARB), -NHCORA, -NRCORA, -NHCONH2, - NHCONRAH, -NHCON(RARB), -NRCCONH2, -NRCCONRAH, -NRCCON(RARB), -C{ Ν Π ) NH2, -C(=NH)-NHRA, -C(=NH)-N(RARB), -C(=NRC)-NH2, -C(=NRC)-NHRA, -C(=NRC)~ N(RARB), -M ! ( '{ Ni l } M l , -M l ( '{ M l ) \ H RA. - H-C(=NH)-N(RARB), -NH---C(=NRC}-- NH¾ -M i ( ( \' R ( } \ ! ! R \ -NH-C(=NRC)-N(RARB), NRDH-C(-NH)-NH2, -NRD-C(=NH)- NHRA, -NRD-C(=NH)-N(RARB), -NRD-C(=NRC)NH2, -\ K ; C( \ iV ) M I R '.. -NRD— C(=NRC)--N(RARB), -NHNH¾ - IM 1 R \ -NHRV, -S02NH¾ -S02NHRA, -S02NRARB, - C S S CI i R \ -CH=CRARB, -CRC=CRARB, -CR( Ci ! R \ -CRC==CRB, -CCR \ -SH, -SOkRA (k is 0, 1 or 2) and -NH-C(=NH)-NH2. Each of RA-R may independently be an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group, for example, an alkyi, benzylic or aryl group. Further, -NRARD, taken together, may form a substituted or unsubstituted non-aromatic heterocyclic group. A non-aromatic heterocyclic group, benzylic group or aryl group may al so have an aliphatic or substituted aliphatic group as a substituent. A substituted aliphatic group may also have a non-aromatic heterocyclic ring, a substituted a non- aromatic heterocyclic ring, benzyl, substituted benzyl, aryl or substituted aryl group as a substituent. A substituted aliphatic, non-aromatic heterocyclic group, substituted aryl, or substituted benzyl group may have more than one substituent.
[00181 J Suitable substituents for heteroaryl ring nitrogen atoms having three covalent bonds to other heteroaryl ring atoms may include -OH and Ci to C 10 alkoxy . Substituted heteroaryl ring nitrogen atoms that have three covalent bonds to other heteroaryl ring atoms are positively charged, which may be balanced by counteranions such as chloride, bromide, formate, acetate and the like. Examples of other suitable counteranions may include counteranions found in the described pharmacologically acceptable salts.
[00182] Suitable substituents for heteroaryl ring nitrogen atoms having two covalent bonds to other heteroaryl ring atoms include alkyl, substituted alkyl (including haloaikyi), phenyl, substituted phenyl, -S(0)2-(aikyl), -S(0)2-NH(alkyl), -S(())2-NH(alkyl)2, and the like.
[00183] Also included are pharmaceutically acceptabl e salts of the compounds described herein. Compounds disclosed herein that possess a sufficiently basic functional group may react with any of a number of organic or inorganic acids to form a salt. Likewise, compounds disclosed herein that possess a sufficiently acidic functional group may react with any of a number of organic or inorganic bases to form a salt. Acids commonly employed to form acid addition salts from compounds with basic groups may include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p- bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such salts may include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, huiyne-l,4-dioate, hexyne-l ,6-dioate, benzoate, chlorobenzoate, methyibenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenyiacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma- hydroxybutyrate, glycol ate, tartrate, methanesuifonate, propanesulfonate, naphthalene- 1- sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of the described compounds may include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like.
[00184] An "effective amount" is the quantity of compound in which a beneficial clinical outcome may be achieved when the compound is administered to a subject suffering from the described parasite. A "beneficial clinical outcome" may include one or more of: a reduction in number of parasites in a subject; a reduction in the rate of parasite growth in a subject; a reduction in parasite consumption of a subject's bodily resources; a reduction in biomarkers, toxins, proteins, peptides, and other biomolecules associated with infection of the subject by the parasite; a reduction in inflammatory, allergic, toxic, disfigurement, or other effects on the subject by the parasite; a reduction in the severity of the symptoms associated with the parasite and/or an increase in the longevity or health of the subject compared with the absence of the treatment.
[00185] The precise amount of compound administered to a subject may depend on the species, iifecycie, of the parasitical infection. The precise amount of compound administered to a subject may also depend on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. A skilled artisan may determine appropriate dosages depending on these and other factors. Effective amounts of the disclosed compounds typically range between about 1 mg/mnr per day and about 10 grams/mm per day, and preferably between 10 mg/mni per day and about 5 grams/mm2.
[00186] The disclosed compounds and pharmaceutical compositions may be administered by any suitable route, including, for example, orally in tablets, pills, gelcaps, lozenges, or suspensions; by parenteral administration. Parenteral administration can include, for example, systemic administration, such as by intramuscular, intravenous, subcutaneous, or intraperitoneal injection. The compounds may also be administered, for example, orally (e.g. , dietary); topically, in the form of creams, sprays, patches, and the like; by inhalation (e.g. , intrabronchial, intranasal, or oral inhalation of an aerosol formulation, by intranasal drops, and the like); via absorption through mucus membranes (e.g., tissues such as oral, nasal, rectal, vaginal, and the like) via, for example, creams, lozenges, sprays, drops, suppositories, and the like); depot preparations; coatings on sutures, bandages, medical devices, and the like. In some embodiments, oral or parenteral administration are exemplary modes of administration. The disclosed compounds may be administered to the subject in conjunction with an acceptable pharmaceutical earner as part of a pharmaceutical composition for treatment of infection by the described parasite. Formulation of the compound to be administered may vary according to the route and vehicle of administration selected (e.g., solution for injection, capsule or tablet for ingestion, and the like). Suitable pharmaceutical carriers may contain inert ingredients that do not interact with the described compound. Standard pharmaceutical formulation techniques may¬ be employed, such as those described in Remington's Pharmaceutical Sciences, 22nd ed., Mack Publishing Company, Easton, PA, 2012. Suitable pharmaceutical earners for parenteral administration may include, for example, sterile water, physiological saline, bacteriostatic saline (e.g., saline containing about 0.9% mg/mL benzyl alcohol, and the like), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like. Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextrin) or tableting compositions are known in the art (Baker, et al., '"Controlled Release of Biological Active Agents," John Wiley and Sons, New York, 1986).
[00187] A "subject" may be any animal subject to infection by the described parasites, e.g., the subject may be a mammal, bird, marsupial, fish, or amphibian. For example, the subject may be a mammal, such as a human. The subject may also be a domestic or wild animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like), laboratory animals (e.g., rats, mice, guinea pigs, and the like), birds, fish, marsupials, and the like. [00188] To the extent that the terra "includes" or ' ncluding" is used in the specification or the claims, it is intended to be inclusive in a manner similar to the term "comprising" as that term is interpreted when employed as a transitional word in a claim. Furthermore, to the extent that the term "or" is employed (e.g., A or B) it is intended to mean "A or B or both." When the applicants intend to indicate "only A or B but not both" then the term "only A or B but not both" will be employed. Thus, use of the term "or" herein is the inclusive, and not the exclusive use. See Bryan A. Garner, A Dictionary of Modern Legal Usage 624 (2d. Ed. 1995). Also, to the extent that the terms "in" or "into" are used in the specification or the claims, it is intended to additionally mean "on" or "onto." To the extent that the term "selectively" is used in the specification or the claims, it is intended to refer to a condition of a component wherein a user of the apparatus may activate or deactivate the feature or function of the component as is necessary or desired in use of the apparatus. To the extent that the term "operatively connected" is used in the specification or the claims, it is intended to mean that the identified components are connected in a way to perform a designated function. To the extent that the term "substantially" is used in the specification or the claims, it is intended to mean that the identified components have the relation or qualities indicated with degree of error as would be acceptable in the subject industry.
[00189] As used in the specification and the claims, the singular forms "a," "an," and
"the" include the plural unless the singular is expressly specified. For example, reference to "a compound" may include a mixture of two or more compounds, as well as a single compound.
[00190] As used herein, the term "about" in conj unction with a number is intended to include ± 1 0% of the number. In other words, "about 10" may mean from 9 to 11. Where the term "about" is used with respect to a number that is an integer, the term "about" may mean ± 10% of the number, or ± 5, ± 4, ± 3, ± 2, or ± 1 of the number.
[00191] As used herein, the terms "optional" and "optionally" mean that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.
[00192] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. As will be understood by one skilled in the ait, for any and ail purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, and the like. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, and the like. As will also be understood by one skilled in the art all language such as "up to," "at least,'" "greater than," "less than," include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. For example, a group having 1-3 members refers to groups having 1 , 2, or 3 members. Similarly, a group having 1-5 members refers to groups having 1, 2, 3, 4, or 5 members, and so forth. While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art.
[00193] As stated above, while the present application has been illustrated by the description of embodiments thereof, and while the embodiments have been described in considerable detail, it is not the intention of the applicants to restrict or in any way limit the scope of the appended claims to such detail. Additional advantages and modifications will readily appear to those skilled in the art, having the benefit of the present application. Therefore, the application, in its broader aspects, is not limited to the specific details, illustrative examples shown, or any apparatus referred to. Departures may be made from such details, examples, and apparatuses without departing from the spirit or scope of the general inventive concept.

Claims

1 . A compound, represented by Structural Formula (la):
(la) Ar— C(=NR1)NR2— A— X— Y- and pharmaceutically acceptable salts thereof, wherein:
Ar is an optionally substituted aryl or nitrogen-containing heteroaryl;
R1 and R are independently H, optionally substituted Cj -Ce alkyl, or optionally substituted C3-C5 cycloaikyl;
A is a bond or an optionally substituted linking moiety comprising 1 , 2, or 3 rings, each ring in the opti onally substituted linking moiety independently being one of: aryl, cycloaikyl, heterocycloalkyl, and heteroaryl;
X is O, S, amide, or a bond;
Y is optionally substituted C Ci4 alkyl or optionally substituted C2-C1 alkenyl; and Het2 is an optionally substituted five-membered nitrogen-containing heteroaroniatic ring comprising 1 , 2, or 3 ring heteroatoms,
provided that the compound represented by Structural Formula (la) is not one of free- base Compounds la-f:
Figure imgf000069_0001
2. The compound of claim 1 , represented by Structural Formula 1
(I) Het4—■C(=NR1)NR2— A— X— \ let*
and pharmaceutically acceptable salts thereof, wherein:
Het* is an optionally substituted, nitrogen-containing heteroaryl;
R3 and R" are independently H, optionally substituted Cj -Ce alkyl, or optionally substituted C3-C5 cycloaikyl; A is a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings, each ring in the optionally substituted linking moiety independently being one of: aryl, cvcloaikyl, heterocycloalkyl, and heteroaryl;
X is O, S, amide, or a bond;
Y is optionally substituted C Cio alkyl or optionally substituted C2-C10 aikenyl; and Het2 is an optionally substituted five-membered nitrogen-containing heteroaroniatic ring comprising 1 , 2, or 3 ring heteroatoms,
provided that the compound represented by Structural Formula (I) is not one of free-base
Compounds la-f:
Figure imgf000070_0001
3. The compound of claim 2, wherein Het1 is optionally substituted pyndyl, pyrazinyl, pyrimidinyl, or pyridizinyl.
4, The compound of claim 2, wherein Met is optionally substituted pyridyl.
s The compound of claim 1 , represented by Structural Formula (II):
-C(=NR1)NR2— A-X-Y— Het2
(II)
The compound of claim 1 , represented by Structural Formula (III):
NH
Hei1 ^N-A-X-Y-Het2
H
7. The compound of claim 2, wherein each ring in the optionally substituted linking moiety represented by A is independently and optionally substituted by one or more of: hydroxy, halo, and Cj-Cf, aikoxy.
8. The compound of claim 2, wherein A comprises an optionally substituted heteroaryl or optionally substituted heteroeycloalky ring,
9. The compound of claim 8, wherein A comprises an optionally substituted, oxygen- containing heteroaryl or heteroeycloalkyi ring.
10. The compound of cl aim 9. w herein A comprises an optionally substituted furanyl or optionally substituted tetrahydrofura ring.
1 1. The compound of claim 9, wherein A comprises optionally substituted 2,5-furanyl.
1 2. The compound of claim 2, wherein A comprises one or two optionally substituted phen l rings.
13. The compound of claim 12, wherein A comprises optionally substituted 1,4-phenyl.
14. The compound of claim 12, wherein A is optionally substituted 1,4-phenyl.
15. The compound of cl aim 12. wherein A is optionally substituted ph enyl -heteroaryl - phenyl.
16. The com ound of claim 1 , represented by one of Structural Formulas (IMa)-(ilii):
Figure imgf000071_0001
wherein Z„ Z[, and 7? are each independently CH or N, n is .1 - 14. and R3 is H, halogen. optionall halogenated Ci~C6 alkyl, or optionally halogenated Ci-Ce alkoxy.
17. The compound of claim 16, wherein the compound is one of Compounds lg-lv:
Figure imgf000071_0002
Figure imgf000072_0001
Figure imgf000073_0001
18. The compound of cl aim 16, wherein the compound is Compound
Figure imgf000073_0002
19. The compound of claim 1 represented by Structural Formula (IV)
Figure imgf000073_0003
wherein each R3 is independently H, halogen, optionally haiogenated Ci-Ce alkyl, or optionally haiogenated Ci-Cr, alkoxy,
20. The compound of claim 1 represented by Structural Formula (V):
Figure imgf000073_0004
wherein each R is independently H, halogen, optionally haiogenated Ci-Ce alkyl, or optionally haiogenated Cj-Cf, alkoxy.
21. The compound of claim 1 , represented by one of Structural Formulas (Va)-(Ve):
Figure imgf000074_0001
wherein Z, Z1, and Z2 are each independently CH or N, n is 1 -14, and R3 is H, halogen, optionally halogenated Ci-C6 alkyl, or opti onally halogenated Ci-C6 alkoxy.
22. The compound of claim 1, wherein Y comprises at least 4 linking atoms between X and Met2.
23. The compound of claim i , w herem X is O or a bond and Y is CrC12 alkyl optionally substituted with one or more of: optionally halogenated Ci-C8 alkyl and optionally halogenated aryl.
24. The compound of claim 1 , represented by Structural Formula (Via):
NH O R4
(Via) H H
wherem R4 is H, optionally halogenated Ci-C8 alkyl, or optionally halogenated aryl.
25. The compound of claim 1 , represented by Structural Formula (Vib): NH O R4
,X ^Het:
(Vib) H H
wherein R* is H, optionally halogenated Ci-C8 alkyl, or optionally halogenated aryl.
26. The compound of claim 2. wherein Het2 comprises an optionally substituted pyrrole, diazole, thiadiazole, oxadiazole. and triazole,
27. The compound of claim 26. wherein Het2 is optionally substituted imidazole optionally substituted 1, 2. 4 triazole.
28. The compound of claim 1 represented by Structural Formula (VII):
Figure imgf000075_0001
wherein:
/. CH or N;
each R3 is independently H, halogen, optionally halogenated Ci-C , alkyl, or opti halogenated Cj-CV, alkoxy: and
ii is an integer from 1 to 10.
The compound of claim 28. wherein the compound is one of Compounds 2a-2h:
Figure imgf000075_0002
Figure imgf000076_0001
Figure imgf000077_0001
PCT/US2017/049491
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
32. The compound of claim 1, wherein the compound is one of Compounds 13a- 13c:
Figure imgf000080_0002
33. The compound of claim 1 represented by Structural Formula (VIII):
Figure imgf000080_0003
wherein:
each R3 is independently H, halogen, Ci~C4 aiky!, or C1-C4 a!koxy: and
ll6 is H, optionally halogenated Cj-CV, alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
The compound of claim 33, wherein the compound is one of Compounds Sa-Sf:
Figure imgf000081_0001
Figure imgf000082_0001
35. The compound of claim 1 , represented by Structural Formula (IX):
Figure imgf000082_0002
wherein:
each R5 is independently H, halogen, C C4 alkyl, or C1-C4 alkoxy; and
R6 is H. optionally halogenated C?-C6
Figure imgf000082_0003
optionally halogenated phenyl, or optionally halogenated biphenyl.
36. The compound of claim 35, wherein the compound is one of Compounds 6a-6f:
Figure imgf000082_0004
Figure imgf000083_0001
37. The compound of claim 1, represented by Structural Formula (X):
Figure imgf000083_0002
wherein:
each R5 is independently H, halogen, C1-C4 alkyl, or C1-C4 alkoxy; and
R6 is H, optionally halogenated C; -C„ optionally halogenated phenyl, or optionally hal ogenated bi ph eny 1 ,
38. The compound of claim 37, wherein the compound is one of Compounds 7a~7f:
Figure imgf000084_0001
39. The com ound of claim 1. represented by Structural Formula (XI):
Figure imgf000084_0002
wherein:
each R5 is independently H. halogen, Cj-C4 alkyl, or C1-C4 alkoxy; and
R° is H. optionally halogenated C i -C6 alkyl, optionally halogenated phenyl, or optional! halogenated bs ph eny 1 ,
40. The compound of claim L represented by Structural Formula (XII):
Figure imgf000085_0001
wherein:
each R5 is independently H, halogen, C1-C alkyl, or C1-C4 alkoxy; and
R6 is H, optionally halogenaied -C6 alkyl, optionally halogenaied phenyl, or optionally halogenaied bipheny ,
41. The compound of claim 2, wherein A is phenyl and X is a bond.
42. The compound of claim 1 , represented by Structural Formula (XIII):
Figure imgf000085_0002
wherein:
Z = CH or N; and
n is an integer from 1 to 10.
The compound of claim 42, wherein
Figure imgf000085_0003
44. The compound of claim 2, wherein A is a bond.
The compound of claim 44, represented by Structural Formula (XIV):
Figure imgf000085_0004
wherein:
Z CH o N; and
n is an integer from 1 to 10.
46. The compound of claim 45, wherein the compound is one of Compounds 9a-'
Figure imgf000086_0001
; compound of claim 1 , represented by Structural Formula (XV)
Figure imgf000086_0002
wherein Z, Z1, and Z2 are each independently CH or N, n is 1-14, and R3 is H, halogen, optionally halogenated Ci-C6 alkyl, or optionally halogenated Ci-C6 al ko\v
48. The compound of claim 47, represented by one of Structural Formulas (XVa)-(XVc):
Figure imgf000086_0003
49. The compound of claim 48, wherein the compound is one of Compounds 10a- 10m:
Figure imgf000086_0004
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
wherein Z, Z1, and Z2 are each independently CH or N, n is 1 -14, and RJ is H, halogen. optionally halogenated Ci~C6 alkyl, or optionally halogenated C]-C6 alkoxy.
51. The compound of claim 50, represented by one of Structural Formulas (XVIa)-(XVIb):
Figure imgf000089_0002
52. The compound of claim 51 , wherein the compound is one of Compounds I la-l ld:
Figure imgf000089_0003
Figure imgf000090_0001
The compound of claim 50, represented by one of Structural Formulas (XVIIa)-(XVIl
nd (XVIIb)
Figure imgf000090_0002
54. The compound of claim 53, wherein the compound is Compound 12a:
Figure imgf000090_0003
55. A method of anti-parasitic treatment for a subject in need thereof, comprising:
providing the subject, the subject being infected by a parasite or at risk of infection by the parasite;
administering a compound to the subject in an amount effective to mitigate infection by the parasite in the subject, the compound being represented by Structural Formula (la):
(la) Ar— C(=N 1)NR2— A— X— Y— Het2
and pharmaceutically acceptable salts thereof, wherein:
Ar is an optionally substituted aryl or nitrogen-containing heteroary I;
R1 and R" are independently H, optionally substituted \~Ce alkyl, or optionally substituted C Ce cycloalkyl;
A is a bond or an optionally substituted linking moiety comprising 1 , 2, or 3 rings, each ring in the optionally substituted linking moiety independently being one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl;
X is O, S, amide, or a bond;
Y is optionally substituted C Ci4 alkyl or optionally substituted C2-C14 alkenyl; and Het2 is an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1 , 2, or 3 ring heteroatoms.
56. The method of claim 55, comprising:
providing the subject, the subject being infected by the parasite or at risk of infection by the parasite;
administering the compound to the subject in an amount effective to mitigate infection by the parasite in the subject, the compound being represented by Structural Formula (I): and pharmaceutically acceptable salts thereof, wherein:
Met1 is an optionally substituted, nitrogen-containing heteroaryl;
R1 and R2 are independently H, optionally substituted Ci-C6 aikyl, or optionally substituted t C , cycloalkyl;
A is a bond or an optionally substituted linking moiety comprising 1 , 2, or 3 rings, each ring in the optionally substituted linking moiety independently being one of: aryl, cycloalkyl, heteroeycloalkyl, and heteroaryl;
X is O, S, amide, or a bond;
Y is optionally substituted C i-Cio alkyl or optionally substituted C2-C19 alkenyl; and Het2 is an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
57. The method of claim 55, provided that when the parasite is L. amazonensis, the compoimd re resented by Structural Formula (la) is not one of free-base Compounds la-f:
Figure imgf000091_0001
58. The method of claim 55, the subject being infected by the parasite, the method comprising administering the compound to the subject in an amount effective to mitigate one or more symptoms of infection by the parasite in the subject.
59. The method of claim 55, the subject being at risk of infection by the parasite, the method comprising administering the compound to the subject in an amount effective to mitigate infection or re-infection of the subject by the parasite.
60. The method of claim 55, the parasite being a kinetopiastid.
61. The method of claim 60, the parasite comprising at least two distinct cytochrome P450 mediated biosterol synthesis pathways.
62. The method of claim 61, the parasite comprising CYP5122A.
63. The method of claim 61, the parasite comprising CYP51 and CYP5122A.
64. The method of claim 55, the parasite belonging to the genus Leishmania.
65. The method of claim 63, the Leishmania parasite being one of: L. aethiopica, L.
amazonensis, L. arabica, L. archibaldi, L. aristedesi, L. Viannia, L. braziliensis, L. chagasi, L. colornbiemis, L. aeanei, L. donovani, L. enriettii, L. equatorensis, L. forattinii, L. garnhami, L. gerbili, L. guyanensis, L. herreri, L. hertigi, L. infantum, L. killicki, L. lainsoni, L. major, L, mexicana, L. naiffi, L. panamensis, L. peruviana, L. pijanoi, L. shawi, L. tarentoiae, L. tropica, L. turanica, and L. venezuelensis.
66. The method of claim 63, wherein the subject suffers from or is at risk of suffering from one or more of: cutaneous leishmaniasis, mucocutaneous leishmaniasis, and visceral leishmaniasis.
67. The method of claim 55, the parasite being of the genus Trypanosoma.
68. The method of claim 67, wherein the Trypanosoma, parasite is one of: T. ambystomae, T. avium, T. boissoni, T. brucei, T. cruzi, T. congolense, T. equinum, T. equiperaum, T. evansi, T. everetti, T. hosei, T. irwini, T. lewisi, T. melophagium, T. paddae, T. parroti, T. percae, T.
rangeli, T. rotatorium, T. rugosae, T. sergenti, T. simiae, T. sinipercae, T. suis, T. theileri, T. triglae, and T. vivax.
69. The method of claim 67, wherein the subject suffers from or is at risk of suffering from: African trypanosomosis, sleeping sickness, Chagas disease, nagana, and surra.
70. The method of claim 55, wherein the subject is a human, dog, cat, cow, horse, sheep, pig, bird, amphibian, or fish.
71. The method of claim 56, wherein Het3 is optionally substituted pyridyl, pyrazinyl, pyrimidinyl, or pyridizmyl.
72. The method of claim 56, wherein Het1 is optionally substituted pyridyl.
73. The method of claim 55, wherein the compound is represented by Structural Formula -C(=NR )NR— A— X— Y— -U Hae+t2
(II)
74. The method of claim 55, wherein the compound is represented by Structural Formula
NH
Hei1^N-A-X-Y-Het2
(III) H
75. The method of claim 55, wherein each ring in the optionally substituted linking moiety represented by A is independently and optionally substituted by one or more of: hydroxy, halo, and Ci-Ce alkoxy.
76. The method of claim 55, wherein A comprises an optionally substituted heteroaryl or optionally substituted heterocycloalkyl ring.
77. The method of claim 55, wherein A comprises an optionally substituted, oxygen- containing, heteroaryl or heterocycloalkyl ring.
78. The method of claim 55, wherein A comprises an optionally substituted furanvl or optionally substituted tetrahydro furanvl ring.
79. The method of claim 55, wherein A comprises optionally substituted 2,5-furanyl,
80. The method of claim 55, wherein A comprises one or two optionally substituted phenyl rings.
81. The method of claim 55, wherein A comprises optionally substituted 1 ,4-phenyl.
82. The method of claim 55, wherein A is optionally substituted 1 ,4-phenyl.
83. The method of claim 55, wherein A is optionally substituted phenyl-heteroaryl-phenyl.
84. The method of claim 55, wherein the compound is represented by one of Structural Formulas Illa)-(IIIf):
Figure imgf000093_0001
Figure imgf000094_0001
wherein Z, Z1, and Z2 are each independently CH or N, n is 1-14, and R3 is H, halogen, optionally halogenated Ci-C* aikyl, or optionally halogenated C]-C aikoxy.
85. The method of claim 84, wherein the compound is one of Compounds la-lv:
Figure imgf000094_0002
Figure imgf000095_0001
-93 -
Figure imgf000096_0001
The method of claim 55, wherein the compound is represented by Structural Formula
Figure imgf000096_0002
wherein each R is independently H, halogen, optionally halogenated Ci-Ce aikyl, or optionally halogenated Ci-Ce alkoxy.
88. The method of claim 55, wherein the compound is represented by Structural Formula
Figure imgf000096_0003
wherein each R is independently H, halogen, optionally halogenated Cj -C6 aikyl, or optionally halogenated C1-C0 alkoxy.
89. The method of claim 55, wherein the compound is represented by one of Structural Formulas (Va)-(Ve :
Figure imgf000096_0004
Figure imgf000097_0001
wherein Z, Z!, and Z2 are each independently CH or N, n is 1-14, and R' is H, halogen, optionally halogenated Ci-Ce alkyl, or optionally halogenated Cj-Ce alkoxy.
90. The compound of claim 1 , wherein Y comprises at least 4 linking atoms between X and
91. The method of claim 55, wherein X is O or a bond and Y is C-.-Ci?. alkyl optionally substituted with one or more of: optionally halogenated Ci-C alkyl and optionally halogenated aryl.
92. The method of claim 55, wherein the compound is represented by Structural Formula
Figure imgf000097_0002
wherein R4 is H, optionally halogenated Cj-Cg alkyl, or optionally halogenated aryl.
93. The method of claim 55, wherein the compound is represented by Structural Formula
Figure imgf000097_0003
wherein R4 is H, optionally halogenated Ci-Cg alkyl, or optionally halogenated aryl
94. The method of claim 56, wherein Het2 comprises an optionally substituted one of:
pyrrole, diazole, thiadiazole, oxadiazole, and triazole.
95. The method of claim 56, wherein Het2 is optionally substituted imidazole or optionally substituted 1 , 2, 4 triazole.
96. The method of claim 55, wherein the compound is represented by Structural Formula (VII):
Figure imgf000098_0001
wherein:
Z CH o N;
each R3 is independently H, halogen, optionally halogenated Ci-C , alkyl, or optionally halogenated Cj-CV, alkoxy: and
ii is an integer from 1 to 10.
97. The method of claim 96, wherein the compound is one of Compoimds 2a-2h:
2
Figure imgf000098_0002
c
Figure imgf000099_0001
Figure imgf000099_0002
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
00. The method of claim 55, wherein the compound is one of Compounds 13a- 13c:
Figure imgf000103_0002
wherein:
each R3 is independently H, halogen, CrC4 alkyl, or Cj-C4 alkoxy; and
R6 is H, optionally halogenated C - -Ce alkyl, optionally halogenated phenyl, or optionally halogenated bi phenyl .
102. The method of claim 101 , wherein the compound is one of Compounds 5a~5f:
Figure imgf000104_0001
Figure imgf000105_0001
103. The method of claim 55, wherein the compound is represented by Structural Formula
Figure imgf000105_0002
wherein:
each R5 is independently H, halogen, Cj-Ct alkyl, or C1-C4 alkoxy; and
R° is H, optionally halogenated C C6 alkyl, optionally halogenated phenyl, or optionally halogenated bipheny 1 ,
104. The method of claim 103, wherein the compound is one of Compounds 6a-6f:
Figure imgf000105_0003
Figure imgf000106_0001
105. The method of claim 55, wherein the compound is represented by Structural Formula (X):
Figure imgf000106_0002
wherein:
s5
each R" is independently H, halogen, Cj-C4 alkyl, or Ci-C4 alkoxy; and
R° is H. optionally halogenated Ci-C6 alkyl, optionally halogenated phenyl, or optionall halogenated biphenyl,
106. The method of claim 105, wherein the compound is one of Compounds 7a-7f:
Figure imgf000107_0001
107. The method of claim 55, wherein the compound is represented by Structural Formula
Figure imgf000107_0002
wherein:
each R3 is independently H, halogen, Ci~C4 alkyl, or C1-C4 a!koxy: and
ll6 is H, optionally halogenated CVC6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
108. The method of claim 55, wherein the compound is represented by Structural Formula
Figure imgf000108_0001
wherein:
each R5 is independently H, halogen, C1-C alkyl, or C1-C4 alkoxy; and
R6 is H, optionally halogenated -C6 alkyl, optionally halogenaied phenyl, or optional! halogenaied bipheny ,
109. The method of claim 55, wherein A is phenyl and X is a bond.
110. The method of claim 55, wherein the compound is represented by Structural Formula (XIII):
Figure imgf000108_0002
wherein:
Z = CH or N; and
n is an integer from 1 to 10.
The method of claim 110, wherein the compound is one of Compound
Figure imgf000108_0003
112. The method of claim 55, wherein A is a bond.
1 13. The method of claim 1 12, wherein the compound is represented by Structural Formula (XIV):
Figure imgf000108_0004
wherein:
Z = CH or N; and
ii is an integer from 1 to 10.
1 14. The method of claim 113, wherein the compound is one of Compounds 9a-9d:
Figure imgf000109_0001
1 15. The method of claim 55, wherein the compound is represented by Structural Formula (XV);
Figure imgf000109_0002
wherein Z, Z1, and Z2 are each independently CH or N, n is 1-14, and R3 is H, halogen, optionally halogenated C]-C(J alkyl, or optionally halogenated C\~C(, alkoxy.
1 16. The method of claim 115, wherein the compound is represented by one of Structural Formulas XVa)-(XVc):
Figure imgf000109_0003
117. The method of claim 1 16, wherein the compound is one of Compounds lOa-iOm:
Figure imgf000110_0001
- 108 -
Figure imgf000111_0001
- 109 -
Figure imgf000112_0001
1 18. The method of claim 55, wherein the compound is represented by one of Structural Formulas (XVI) and XVII):
Figure imgf000112_0002
wherein Z, Z1, and Z2 are each independently CH or N, n is 1-14, and R3 is H, halogen, optionally halogenated Cj -Ce alkyl, or optionally halogenated Ci-C alkoxy.
1 19. The method of claim 1 8, wherein the compound is represented by one of Structural Formulas (X -(XVIb):
Figure imgf000112_0003
120. The method of claim 1 19, wherein the compound is one of Compounds lla-lld:
Figure imgf000113_0001
121. The method of claim 55, wherein the compound is represented by one of Structural Formulas (XVIIa)~(XVIIb);
Figure imgf000113_0002
122. The method of claim 123, wherein the compound is Compound 12a:
Figure imgf000113_0003
123. A kit for anti-parasite treatment of a subject in need thereof, comprising;
a compound represented by Structural Formula (I):
(la) Ar C(=NR1)NR2 A- X-
- I l l - pharmaceuti cally acceptable salts thereof, and mixtures thereof with a pharmaceutically acceptable carrier or excipient, wherein:
Ar is an optionally substituted aryl or nitrogen-containing heteroaryl;
1 and R2 are independently H, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl;
A is a bond or an optionally substituted linking moiety comprising 1 , 2, or 3 rings, each ring in the optionaily substituted linking moiety independently being one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl;
X is O, S, amide, or a bond;
Y is optionally substituted Cj -Ci4 alkyl or optionally substituted C2-C 14 alkenyl; and
Met2 is an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1 , 2, or 3 ring heteroatoms; and
instructions, the instructions directing a user to:
provide the subject, the subject being infected by a parasite or at risk of infection by the parasite; and
administer the compound or the pharmaceutical composition to the subject in an amount effective to mitigate infection by the parasite in the subject.
124. The kit for anti-parasite treatment of claim 123, the compound being the compound of any of claims 1-54.
125. The kit for anti-parasite treatment of claim 123, the instructions directing the user to conduct the method of any of claims 55-122.
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