WO2019174279A1 - Dérivés de 1,2-benzisosélénazol-3(2h)-one et de 1,2-benzisothiazol-3(2h)-one utilisés comme adjuvants d'antibiotiques bêta-lactame - Google Patents

Dérivés de 1,2-benzisosélénazol-3(2h)-one et de 1,2-benzisothiazol-3(2h)-one utilisés comme adjuvants d'antibiotiques bêta-lactame Download PDF

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WO2019174279A1
WO2019174279A1 PCT/CN2018/114268 CN2018114268W WO2019174279A1 WO 2019174279 A1 WO2019174279 A1 WO 2019174279A1 CN 2018114268 W CN2018114268 W CN 2018114268W WO 2019174279 A1 WO2019174279 A1 WO 2019174279A1
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compound
nmr
aryl
hydrogen
mmol
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Sheng Chen
Kin-Fai Chan
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The Hong Kong Polytechnic University
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D293/00—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms
    • C07D293/10—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D293/12—Selenazoles; Hydrogenated selenazoles
    • 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

  • Carbapenem-resistant Enterobacteriaceae comprise a family of Gram-negative bacteria that exhibit antimicrobial resistance to multiple antibiotics, notably carbapenems, which are the drugs of last resort for treating lethal infections.
  • CRE are the major causes of community-and healthcare-associated bacterial infections, such as those in the urinary tract, bloodstream, surgical site, and intra-abdominal region. Because of their phenotypic resistance to various antibiotics, infections due to such “nightmare bacteria” are often difficult to treat, resulting in a significantly increased mortality.
  • carbapenemases which are carbapenem-hydrolyzing beta-lactamases that possess versatile hydrolytic capacities to break down nearly all beta-lactam antibiotics and render them ineffective.
  • carbapenemases belong to members of the class A, B, and D beta-lactamases, among which the most efficient carbapenemases are class B metallo-beta-lactamases (MBLs) .
  • MBLs employ a central zinc ion as essential cofactor to catalyze hydrolysis of the beta-lactam ring.
  • MBLs can be further divided into three subclasses (B1, B2 and B3) according to their amino acid sequence.
  • NDM-1 New Delhi metallo-beta-lactamase-1 (NDM-1) of subclass B1 MBLs contains a dinuclear zinc center and a water molecule in the active site, in which both zinc ions are coordinated with the 3H site (His116, His118, His196) and the DCH site (Asp120, Cys221, His263) , and the water molecule is located in between both zinc ions.
  • subclass B1 MBLs are the most significant and prevalent carbapenemases, particularly, NDM-1.
  • the rapid worldwide dissemination of NDM-1-producing “superbugs” further emphasizes the significant role of this type of carbapenemases in conferring antimicrobial resistance, and a pressing need for development of effective NDM-1 inhibitors for clinical applications.
  • NDM-1-producing K. pneumoniae isolate in year 2009, huge success has been made in combating organisms that produce beta-lactamases through clinical usage of beta-lactam antibiotic/beta-lactamase inhibitor combinations.
  • development of small molecules targeting NDM-1 have been actively pursued in the past decade.
  • Numerous reports on construction of NDM-1 inhibitors and covalent inhibitors have appeared in the literature.
  • clinically useful inhibitors of MBLs, in particular NDM-1 are still not available. Thus, there is a need to develop additional useful NDM-1 inhibitors.
  • compositions and methods useful in the treatment of bacterial infections when administered alone or co-administered with a beta-lactam antibiotic are useful as inhibitors of various beta-lactamases, such as NDM-1, and in certain embodiments possess antibacterial properties.
  • a method of treating a bacterial infection in a patient in need thereof comprising the step of co-administering a pharmaceutically effective amount of a beta-lactam antibiotic and a compound of formula I to the patient, wherein the compound of formula I has the structure:
  • X is S or Se
  • R 6 for each instance is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl; or two instances of R 6 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyloalkyl;
  • R 7 independently for each instance is hydrogen, alkyl, cycloalkyl, heterocycloalkyl aryl, araalkyl, or heteroaryl;
  • R 9 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, and – (CR 7 ) n CO 2 H; or two instances of R 9 taken together with the atoms to which they are covalently bonded form a 3-6 membered heterocyloalky; and
  • n for each occurrence is independently an integer selected from 1-6, with the proviso that when R 1 , R 2 , R 3 , and R 4 are hydrogen, R 5 is not phenyl.
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halide, nitrile, nitro, hydroxyl, and alkyl.
  • X is Se
  • R 5 is – (CR 7 ) n R 8
  • R 9 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, and – (CR 7 ) n CO 2 H.
  • R 5 is selected from the group consisting of:
  • R 1 , R 2 , R 3 , and R 4 are hydrogen.
  • X is Se
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halide, nitrile, nitro, hydroxyl, and alkyl
  • R 5 is selected from the group consisting of:
  • R 1 , R 2 , R 3 , and R 4 are hydrogen.
  • X is S and R 5 is aryl, -SO 2 R 9 , or – (CR 7 ) n R 8 , wherein n is 1, 2, or 3.
  • R 5 is phenyl, 4-substituted aryl, 3-substituted aryl, or 3, 4-disubsitituted aryl.
  • R 5 is selected from the group consisting of:
  • bacterial infection is caused by a bacteria that expresses a carbapenemase beta-lactamase or a penicillinase.
  • bacterial infection is caused by a bacteria that expresses New Delhi metallo-beta-lactamase 1.
  • the method of the first aspect wherein the bacterial infection is caused by bacteria from the genus Staphylococcus, Micrococcus, Bacillus, Listerella, Escherichia, Klebsiella, Proteus, Salmonella, Shigella, Enterobacter, Serratia, Pseudomonas, Acinetobacter, Nocardia, or Mycobacterium.
  • the beta-lactam antibiotic is a carbapenem and the compound of formula I has the structure:
  • Figure 1 depicts a schematic illustrating compound 11_a38 and its inhibitory action on NDM-1
  • FIG. 2 depicts the active site of NDM-1 and various NDB-1 inhibitors.
  • Figure 3 depicts the Kaplan-Meier survival analysis of monotherapy with 11_a38 or meropenem (Mem) and combination therapy with 11_a38 and Mem in protecting Galleria mellonella larvae infected with a lethal dose of the clinical NDM-1-producing CRE isolate EL10 (2.5 x 10 5 CFU/larva) . Data are the means of three independent experiments.
  • Figure 4 depicts compound 11_a38 exhibiting in vitro dose-dependent inhibition of NDM-1 enzyme with an IC 50 of 13 ⁇ M.
  • Figure 5 depicts (A) Time-dependent and concentration-dependent inhibition of NDM-1 enzyme by compound 11_a38; (B) Hyperbolic plot of K obs of compound 11_a38 versus concentration of compound 11_a38.
  • Figure 6 depicts Residual activity of NDM-1 enzyme after rapid high dilution of enzyme-compound 11_a38 complex.
  • Figure 7 depicts the tolerability of Galleria mellonella larvae treated with compound 11_a38.
  • Figure 8 depicts the nano-ESI-MS analysis and their cartoon representations of wild-type (A) and denatured (C) NDM-1 enzyme as well as compound 11_a38-treated wild-type (B) and denatured (D) NDM-1 enzyme.
  • Figure 9 depicts the cytotoxicity profile of compound 11_a38 against HeLa and L929 cell lines.
  • Figure 10 depicts HPLC chromatogram of compound 11_a38 under the following HPLC conditions: Column: Agilent Prep-Sil Scalar column (4.6 x 250 mm, 5- ⁇ m) ; Temperature: room temperature (23°C) ; Flow rate: 1 mL/min; UV detection: 256 nm (reference 450 nm) ; Mobile phase: 96%DCM, 4%methanol; Retention time: 9.22 min; Purity: 98%.
  • Figure 11 depicts HPLC chromatogram of compound 3a under the following HPLC conditions: HPLC conditions: Column: Agilent Prep-Sil Scalar column (4.6 x 250 mm, 5- ⁇ m) ; Temperature: 23°C; Flow rate: 1 mL/min; UV detection: 256 nm (reference 450 nm) ; Mobile phase: 98%DCM, 2%methanol; Retention time: 9.364 min; Purity: 99.7%.
  • HPLC conditions Column: Agilent Prep-Sil Scalar column (4.6 x 250 mm, 5- ⁇ m) ; Temperature: 23°C; Flow rate: 1 mL/min; UV detection: 256 nm (reference 450 nm) ; Mobile phase: 98%DCM, 2%methanol; Retention time: 9.364 min; Purity: 99.7%.
  • Figure 12 depicts the residual activity after fast dilution of enzyme-inhibitor 3a complex.
  • Figure 13 depicts a plot of velosity of NDM-1 against nitrocefin concentration with different concentrations of compound 3a.
  • Figure 14 depicts a bar graph showing the mammalian cytotoxicity of compound 3a against HEK-293T cell lines.
  • Figure 15 depicts compound 3a exhibiting in vitro dose-dependent inhibition of NDM-1 enzyme.
  • the present disclosure generally relates to 1, 2-benzisoselenazol-3 (2H) -one and 1, 2-benzisothiazol-3 (2H) -one analogs their methods of making and intermediates thereto.
  • the present disclosure also provides methods of use of these compounds in the inhibition of beta-lactamases, such as NDM-1.
  • the present disclosure also provides method of treating bacterial infections using the compounds described herein.
  • the compound described herein have been found to be useful in treating antibiotic resistant strains of bacteria and more particularly antibiotic strains of bacteria in which the bacteria expresses one or more beta-lactamases.
  • amino acid refers to molecules containing both a carboxylic acid moiety and an amino moiety.
  • carboxylic acid and amino moieties are as defined below. Both naturally occurring and synthetically derived amino acids are encompassed in the scope of this invention.
  • heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for straight chain, C 3 -C 30 for branched chain) , and alternatively, about 20 or fewer.
  • cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
  • lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • aralkyl is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group) .
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aryl is art-recognized and refers to 5-, 6-and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl heterocycles or "heteroaromatics.
  • the aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN, or the like.
  • substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings” ) wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • ortho, meta and para are art-recognized and refer to 1, 2-, 1, 3-and 1, 4-disubstituted benzenes, respectively.
  • the names 1, 2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
  • heterocyclyl refers to 3-to about 10-membered ring structures, alternatively 3-to about 7-membered rings, whose ring structures include one to four heteroatoms.
  • Heterocycles may also be polycycles.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
  • the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • optionally substituted refers to a chemical group, such as alkyl, cycloalkyl aryl, and the like, wherein one or more hydrogen may be replaced with a with a substituent as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN, or the like
  • nitro is art-recognized and refers to NO 2 ;
  • halogen is art-recognized and refers to -F, -Cl, -Br or -I;
  • sulfhydryl is art-recognized and refers to -SH;
  • hydroxyl means -OH;
  • sulfonyl is art-recognized and refers to -SO 2 -.
  • Halide designates the corresponding anion of the halogens, and "pseudohalide” has the definition set forth on 560 of "Advanced Inorganic Chemistry” by Cotton and Wilkinson.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:
  • R 50 , R 51 and R 52 each independently represent a hydrogen, an alkyl, an alkenyl, - (CH 2 ) m R 61 , or R 50 and R 51 , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
  • R 61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
  • R 50 and R 51 (and optionally R 52 ) each independently represent a hydrogen, an alkyl, an alkenyl, or - (CH 2 ) m R 61 .
  • alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R 50 and R 51 is an alkyl group.
  • alkoxyl or "alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O- (CH 2 ) m R 61 , where m and R 61 are described above.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis-and trans-isomers, R-and S-enantiomers, diastereomers, (D) -isomers, (L) -isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • Suitable pharmaceutically acceptable salts of compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, acetic acid, citric acid, tartaric acid, phosphoric acid, carbonic acid, or the like.
  • a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, acetic acid, citric acid, tartaric acid, phosphoric acid, carbonic acid, or the like.
  • pharmaceutically acceptable salts may be formed by treatment of a solution of the compound with a solution of a pharmaceutically acceptable base, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, tetraalkylammonium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, ammonia, alkylamines, or the like.
  • a pharmaceutically acceptable base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, tetraalkylammonium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, ammonia, alkylamines, or the like.
  • subject refers to an animal, typically a mammal or a human, that will be or has been the object of treatment, observation, and/or experiment.
  • subject refers to an animal, typically a mammal or a human, that will be or has been the object of treatment, observation, and/or experiment.
  • the term is used in conjunction with administration of a compound or drug, then the subject has been the object of treatment, observation, and/or administration of the compound or drug.
  • co-administration and “co-administering” refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents) , as long as the therapeutic agents are present in the patient to some extent at the same time.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a cell culture, tissue system, animal, or human that is being sought by a researcher, veterinarian, clinician, or physician, which includes alleviation of the symptoms of the disease, condition, or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable carrier refers to a medium that is used to prepare a desired dosage form of a compound.
  • a pharmaceutically acceptable carrier can include one or more solvents, diluents, or other liquid vehicles; dispersion or suspension aids; surface active agents; isotonic agents; thickening or emulsifying agents; preservatives; solid binders; lubricants; and the like.
  • CRE carbapenem-resistant Enterobacteriaceae
  • CDC Centers for Diseases Control and Prevention
  • WHO World Health Organization
  • MBLs metallo-beta-lactamases
  • NDM-1 New Delhi metallo-beta-lactamase-1
  • Eb ebselen
  • IPTG isopropyl-beta-D-thiogalactoside
  • Mem meropenem
  • MIC minimum inhibition concentration
  • FIC fractional inhibitory concentration
  • SAR structure-activity relationship
  • ESI-MS electrospray ionization mass spectrometry
  • DMF dimethylformamide
  • EDCI N-ethyl-N’- (3-dimethylaminopropyl) carbodiimide
  • DCM dichloromethane
  • CLSI Clinical and Laboratory Standards Institute.
  • the present disclosure provides a compound of formula I:
  • X is S or Se
  • R 6 for each instance is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl; or two instances of R 6 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyloalkyl;
  • R 7 independently for each instance is hydrogen, alkyl, cycloalkyl, heterocycloalkyl aryl, araalkyl, or heteroaryl;
  • R 9 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, and – (CR 7 ) n CO 2 H; or two instances of R 9 taken together with the atoms to which they are covalently bonded form a 3-6 membered heterocyloalky; and
  • n for each occurrence is independently an integer selected from 1-6.
  • the compound of Formula I does not include ebselen, i.e., if R 1 , R 2 , R 3 , and R 4 are hydrogen, R 5 cannot be phenyl.
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halide, nitrile, nitro, hydroxyl, and alkyl.
  • X is Se
  • R 5 is – (CR 7 ) n R 8
  • R 9 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, and – (CR 7 ) n CO 2 H.
  • X is Se
  • n is 2, 3, or 4
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halide, nitrile, nitro, hydroxyl, and alkyl
  • R 5 is or – (CR 7 ) n R 8
  • R 7 for each instance is independently selected from the group consisting of hydrogen and alkyl
  • R 5 is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • X is Se
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halide, nitrile, nitro, hydroxyl, and alkyl
  • R 5 is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • X is S and R 5 is aryl, -SO 2 R 9 , or – (CR 7 ) n R 8 , wherein n is 1, 2, or 3.
  • R 5 is phenyl, 4-substituted aryl, 3-substituted aryl, or 3, 4-disubsitituted aryl.
  • R 5 is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • R 5 is– (CR 7 ) n R 8 ;
  • R 6 for each instance is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl; or two instances of R 6 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyloalkyl;
  • R 7 independently for each instance is hydrogen, alkyl, cycloalkyl, heterocycloalkyl aryl, araalkyl, or heteroaryl;
  • R 9 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl; or two instances of R 9 taken together with the atoms to which they are covalently bonded form a 3-6 membered heterocyloalky; and
  • n for each occurrence is independently an integer selected from 1-6.
  • n 1-3.
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halide, nitrile, nitro, hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl.
  • R 9 for each instance is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl; or two instances of R 9 taken together with the atoms to which they are covalently bonded form a 3-6 membered heterocyloalky.
  • R 9 for each instance is independently selected from the group consisting of hydrogen and alkyl; or two instances of R 9 taken together with the atoms to which they are covalently bonded form a 3-6 membered heterocyloalky.
  • the compound of formula II has the following formula:
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halide, nitrile, nitro, hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, and -N (R 6 ) 2 ;
  • R 5 is – (CR 7 ) 2 R 8 ;
  • R 6 for each instance is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl; or two instances of R 6 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyloalkyl;
  • R 7 independently for each instance is hydrogen and alkyl
  • R 9 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl.
  • three derivatives of 11 were selected for further functionalization, such as alkylation of 11_a36 with 1-butyl iodide in DMF to furnish 11 with an imidazolium moiety, and acidic deprotection of Boc group of 11_a38 and 11_a39 to yield 11 with an amine group.
  • These amine derivatives were in turn converted to the desired carbamates derivatives 11_a43-11_a45 via standard carbamoylation procedure with 3-methyl-1- ( ( (1, 1, 1-trifluoro-2-methylpropan-2-yl) oxy) carbonyl) -1H-imidazol-3-ium iodide or benzyl chloroformate.
  • Reagents and reaction condition (a) oxalyl chloride, DMF (cat. ) , DCM, rt., 3h. (b) i: amine (excess) , triethylamine, DCM, 0 °C to rt., overnight; ii: Br 2 , DCM, 0 °C to rt., overnight.
  • the present disclosure also provides a pharmaceutical composition comprising any one of the aforementioned compounds and at least one pharmaceutically acceptable excipient.
  • the compounds described herein and their pharmaceutically acceptable salts are can be administered to a mammalian subject either alone or in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, preferably parenterally.
  • Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical, the preferred method being intravenous administration.
  • compositions which comprise a therapeutically-effective amount of one or more of the compounds described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; and (2) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions) , tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue.
  • the preferred method of administration of compounds of the present invention is parental administration (intravenous) .
  • certain embodiments of the compounds described hrein may contain a basic functional group, such as amino or alkylaamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • the pharmaceutically acceptable salts of the compounds of the present disclosure include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from nontoxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compounds described herein may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, solubilizing agents, buffers and antioxidants can also be present in the compositions.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound described herein with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers (liquid formulation) , liquid carriers followed by lyophylization (powder formulation for reconstitution with sterile water or the like) , or finely divided solid carriers, or both, and then, if necessary, shaping or packaging the product.
  • compositions of the present disclosure suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, chelating agents, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • the active ingredients are brought together with the pharmaceutically acceptable carriers in solution and then lyophilized to yield a dry powder.
  • the dry powder is packaged in unit dosage form and then reconstituted for parental administration by adding a sterile solution, such as water or normal saline, to the powder.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) , and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms upon the compounds of the present invention may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • the present disclosure provides methods of treating bacterial infection, wherein the compounds and compositions described herein are used in combination with at least one beta-lactam antibiotic.
  • compositions described herein are particularly useful for treating bacterial infections caused by bacteria that express a beta lactamase, such as by a carbapenemase or a penicillinase.
  • the beta lactamase can be selected from TEM, SHV, CTX-M TEM, OXA TEM, PER, VEB, GES, IBC, IMP, VIM, KPC, and SME beta-lactamases
  • the beta lactamase is selected from the group consisting of VIM-1, IMP-4, KPC-2, CTX-M-3, CTX-M-14, CTX-M-15, TEM-1, SHV-12, and NDM-1.
  • a method of inhibiting a beta lactamase comprising contacting the beta lactamase with at least one of the compounds described herein.
  • the compounds and methods described herein can be used to treat bacterial infection caused by bacteria other than E. coli, such as for example, bacteria from the genus Staphylococcus, such as Staphylococcus aureus or Staphylococcus epidermidis, Streptococcus, such as Streptococcus agalactiae, Streptococcus pneumoniae or Streptococcus faecalis, Micrococcus, such as Micrococcus luteus, Bacillus, such as Bacillus subtilis, Listerella, such as Listerella monocytogene, other members of the Escherichia genus, Klebsiella, such as Klebsiella pneumoniae, Proteus, such as Proteus mirabilis or Proteus vulgaris, Salmonella, such as Salmonella typhosa, Shigella, such as Shigella sonnef, Enterobacter, such as Enterobacter aerogenes or Enterobacter cloacae, Ser
  • beta-lactam antibiotics that can be used in combination with the methods of the present disclosure include, in general beta-lactams comprising penam, carbapenam, oxapenam, penem, carbapenem, monobactam, cephem, carbacephem, or oxacephem cores as shown below.
  • Particularly useful members of those classes include, for example, penams, such as Benzylpenicillin (G) , Benzathine Benzylpenicillin, Procaine Benzylpenicillin, Phenoxymethylpenicillin (V) , Propicillin, Pheneticillin, Pzidocillin, Plometocillin, Penamecilli, Cloxacillin, Dicloxacillin, Flucloxacillin, Oxacillin, Nafcillin, Methicillin, Amoxicillin, Ampicilli, Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin, Epicillin, Ticarcillin Carbenicillin, Carindacillin, Temocillin, Piperacillin, Azlocillin, Mezlocillin, Mecillinam, Pivmecillinam, and Sulbenicillin, penems, such as Faropenem and Ritipenem, carbapenem, such as Ertapenem, Doripenem, Imi
  • the compounds described herein can be co-administered with two more beta-lactam antibiotics.
  • the compounds described herein can be co-administered with a beta-lactam antibiotic and an additional beta-lactamase inhibitor.
  • the additional beta-lactamase inhibitor can be selected from the group consisting of Sulbactam, Tazobactam, Clavulanic acid) , Avibactam, and Vaborbactam.
  • the compounds described herein can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the compounds described herein and the beta-lactam antibiotic can be varied depending on the disease being treated and the known effects of the beta-lactam antibiotic on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e., beta-lactam antibiotic) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
  • the administered therapeutic agents i.e., beta-lactam antibiotic
  • compounds described herein and the beta-lactam antibiotic do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes.
  • compounds described herein may be administered intravenously to generate and maintain good blood levels, while the beta-lactam antibiotic may be administered orally.
  • the determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician.
  • the initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
  • beta-lactam antibiotic will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.
  • a compound described and beta-lactam antibiotic may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the bacterial infection, the condition of the patient, and the actual choice of beta-lactam antibiotic to be administered in conjunction (i.e., within a single treatment protocol) with a compound described herein.
  • the optimum order of administration of the compound described herein and the beta-lactam antibiotic may be different for different bacterial infections.
  • the compound described herein may be administered first followed by the administration of the beta-lactam antibiotic; and in other situations the beta-lactam antibiotic may be administered first followed by the administration of a compound described herein.
  • This alternate administration may be repeated during a single treatment protocol.
  • the determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.
  • the beta-lactam antibiotic may be administered first and then the treatment continued with the administration of a compound described herein followed, where determined advantageous, by the administration of the beta-lactam antibiotic, and so on until the treatment protocol is complete.
  • the practicing physician can modify each protocol for the administration of a component (compound described herein and beta-lactam antibiotic) of the treatment according to the individual patient's needs, as the treatment proceeds.
  • E. coli Tg1 To generate a Mem resistant strain with a clean background for preliminary screening of compounds, a parental E. coli Tg1 strain was transformed into a resistant strain of E. coli Tg1 (NDM-1) by introducing a full-length bla NDM-1 beta-lactamase gene isolated from a clinical K. pneumoniae isolate.
  • E. coli Tg1 (NDM-1) is believed to better mimic clinical CRE strain than E. coli BL21 (NDM-1) .
  • CLSI Clinical and Laboratory Standards Institute
  • the antimicrobial activities of all compounds were evaluated by measuring the MICs against this screening strain, and the results for the 1, 2-benzisoselenazol-3 (2H) -one analogs are presented in Table 1 and the and 1, 2-Benzisothiazol-3 (2H) -one analogs in Table 2.
  • a Compound cLogP were calculated using ChemDraw Ultra (Version 12.0) .
  • the synergistic effect is determined by the FIC index, which is calculated as FIC (cpd) + FIC (Mem) , where FIC (cpd) is the (MIC of cpd in combination with Mem) / (MIC of cpd alone) while FIC (Mem) is (MIC of cpd in combination with Mem) / (MIC of Mem alone) .
  • the drug combination is considered synergistic if the FIC Index is ⁇ 0.5.
  • Synergistic efficiency is calculated by measuring –ln(FIC index) /non-hydrogen atom. N. A. : Not Applicable. All experiments were performed in at least triplicates and inhibition of bacterial growth was assessed by naked eye upon incubation overnight.
  • synergistic efficiency is a normalized FIC index to enable comparisons of synergistic activities between different molecular scaffolds but with the same FIC index. The larger the value of the synergistic efficiency, the stronger the synergistic interaction will be. It provides a useful parameter for medicinal chemists to choose a lead compound for further optimization.
  • Table 1 The results of Mem MICs when tested in combination with the compounds, cLogP, calculated FIC indices and synergistic efficiencies of all compounds are summarized in Table 1, in which compounds were prioritized according to the FIC indices and synergistic efficiency respectively.
  • the parental compound Eb was used as a positive control for comparison purpose.
  • the MIC of Mem in combination with Eb was 16 ⁇ g/mL with a calculated FIC index of 0.50 and synergistic efficiency of 0.043 (Table 1, entry 2) , exhibiting only moderate synergistic activity. Generally, most of the compounds were found to exhibit stronger synergistic activity than Eb, with FIC indices ranging from 0.047 to 0.375. These compounds were divided into two series to investigate their SARs: (1) 1, 2-benzisoselenazol-3 (2H) -one derivatives with a 2-aryl or benzyl side chain and (2) 1, 2-benzisoselenazol-3 (2H) -one derivatives with a flexible 2-alkyl side chain.
  • the bulky Boc group of 11_a38 may be essential in conferring synergistic activity as its replacement with other functional groups, such as 3, 3-dimethylbutanone (Entry 7) , benzyl group (Entry 8) , 2-thiophenylmethone (Entry 10) , dimethylphosphonate (Entry 12) , trifluoro-Boc (Entry 16) , benzyl carbamate (Entry 30) and substituted phenylmethanones (Entry 14, 27, 34) , resulted in weaker synergistic activities.
  • other functional groups such as 3, 3-dimethylbutanone (Entry 7) , benzyl group (Entry 8) , 2-thiophenylmethone (Entry 10) , dimethylphosphonate (Entry 12) , trifluoro-Boc (Entry 16) , benzyl carbamate (Entry 30) and substituted phenylmethanones (Entry 14, 27, 34) ,
  • cLogP and tPSA were calculated by ChemDraw Ultra (Version 12.0) .
  • FICI was defined as FIC (cpd) + FIC (Mem) , where FIC (cpd) was the ratio of MIC combination to MIC cpd and FIC (Mem) was the ratio of MIC combination to MIC Mem .
  • MIC value was determined with naked eye using the double dilution method at least triplicate.
  • SE Synergistic efficiency, it was calculated by –ln (FIC) /non-hydrogen atom. N. A. : Not Applicable.
  • N 1-3 independent experiments.
  • a EC Escherichia coli; KO, Klebsiella oxytoca; CF, Citrobacter freundii; EL, Enterobacter cloacae; KP, Klebsiella pneumoniae; MM, Morganella morganii. Additional beta-lactamase determinants: b1: VIM-1, b2: IMP-4, b3: KPC-2, b4: CTX-M-3, b5: CTX-M-14, b6: CTX-M-15, b7: TEM-1, and b8: SHV-12.
  • the synergistic effect is depicted by the FIC index, which is calculated as FIC (cpd) + FIC (Mem) , where FIC (cpd) is the (MIC of cpd in combination with Mem) / (MIC of cpd alone) while FIC (Mem) is (MIC of cpd in combination with Mem) / (MIC of Mem alone) .
  • the drug combination is considered synergistic if the FIC Index ⁇ 0.5. All experiments were performed in at least triplicates; the degree of inhibition of bacterial growth was determined with the naked eye after incubation.
  • NDM-1-producing strains including four E. coli, two K. oxytoca, four C. freundii, nine E. cloacae, two K. pneumoniae and two M. morganii strains. These CRE strains were all NDM-1 positive and highly Mem resistant, with half of the strains exhibiting Mem MICs ⁇ 128 ⁇ g/mL (Table 3) .
  • CRE strains were all NDM-1 positive and highly Mem resistant, with half of the strains exhibiting Mem MICs ⁇ 128 ⁇ g/mL (Table 3) .
  • beta-lactamases such as VIM-1, IMP-4, KPC-2, CTX-M-3, CTX-M-14, CTX-M-15, TEM-1 and SHV-12.
  • the deconvoluted ESI-MS spectra of compound 11_a38-treated wild-type and denatured NDM-1 protein revealed a complex where the majority of protein had a mass of 26, 272 Da and 26, 208 Da respectively, with a difference of 64 Da, indicating that there was only one zinc ion in the compound 11_a38-treated wild-type NDM-1 protein. Since the molecular mass of compound 11_a38 is about 341 and there is only one cysteine present in the NDM-1 protein, the protein mass difference between the denatured NDM-1 protein and compound 11_a38-treated denatured NDM-1 protein is 342 Da, indicating that only one covalent interaction event occurred between compound 11_a38 and a cysteine molecule.
  • the major peak (26, 272 Da) in the deconvoluted ESI-MS spectra of compound 11_a38-treated wild-type NDM-1 protein therefore, represented the sum of the molecular mass of a denatured NDM-1 protein (25, 866 Da) , compound 11_a38 (341 Da) and one zinc ion (65 Da) . These results are consistent with those of the parental compound Eb.
  • compound 11_a38 exhibited relatively low cytotoxicity against Hela and L929 cell lines, with a cell viability of 70%or higher at a concentration of 2 mg/mL, which is the effective synergistic concentration in the combination study. Microscopic investigation of both cell lines also indicated that there were no morphological changes after incubation with compound 11_a38 at these concentrations, displaying negligible cytotoxicity.
  • the plates used for analytical thin-layer chromatography were E. Merck Silica Gel 60F 254 aluminum-backed plates (0.25 mm thickness) and were visualized under short and long UV light (254 and 365 nm) or stained with acidified potassium permanganate solution followed by gentle heating.
  • Column chromatographic purifications were carried out on MN silica gel 60 (230-400 mesh) with gradient elution.
  • Compound purity was determined by an Agilent 1100 series HPLC installed with a normal phase Prep-Sil Scalar column (4.6 mm ⁇ 250 mm, 5 ⁇ m) at UV detection of 254 nm (reference at 450 nm) . All tested compounds were shown to have >95%purity according to the HPLC.
  • Amines a1-a19, a22-a24, a26-a29, a33, a35-a39, anthranilic acid (8) and 3, 3'-diselanediyldipropanoic acid (9b) are commercially available.
  • Anthranilic acid (8) (18 g, 131 mmol) was dissolved in a solution of 37%hydrochloric acid (30 mL) and H 2 O (30 mL) . After the solution was cooled to 0 °C, a solution of NaNO 2 (10 g, 145 mmol in 10 mL H 2 O) was added dropwise and the reaction mixture was stirred at 0 °C for 30 mins until all solid has been dissolved. The obtained diazonium salt was used immediately without further purification.
  • the starting material 2, 2’-dithiodibenzoyl chloride, was synthesized using known methods. To a solution of corresponding amine (14.5 mmol) in dry dichloromethane (25 mL) was added dropwise a solution of 2, 2’-dithiodibenzoyl chloride (1 g, 2.9 mmol) at 0 °C with stirring. The resulting mixture was allowed to slowly warm to room temperature and was stirred at room temperature overnight. Removal of the organic layer under reduced pressure gave a reddish residue. An aqueous 3 M HCl (20 mL) solution was then poured into the residue to remove the excess amine compounds.
  • This compound (0.20 g, yield 75%) was prepared from 2, 2'-disulfanediylbis (N- (4-chlorophenyl) benzamide) (0.52 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.13 g, yield 43%) was prepared from 2, 2'-disulfanediylbis (N- (4-bromophenyl) benzamide) (0.61 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.12 g, yield 41%) was prepared from 2, 2'-disulfanediylbis (N- (4-(trifluoromethyl) ) benzamide) (0.59 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.11 g, yield 39%) was prepared from 2, 2'-disulfanediylbis (N- (3, 4-dichlorophenyl) benzamide) (0.59 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.14 g, yield 52%) was prepared from 2, 2'-disulfanediylbis (N- (3-chlorophenyl) benzamide) (0.52 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.09 g, yield 38%) was prepared from 2, 2'-disulfanediylbis (N- (2-fluorophenyl) benzamide) (0.49 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.13 g, yield 49%) was prepared from 2, 2'-disulfanediylbis (N- (4- (hydroxymethyl) phenyl) benzamide) (0.52 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.15 g, yield 53%) was prepared from 2, 2'-disulfanediylbis (N- (4-chlorophenethyl) benzamide) (0.58 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.16 g, yield 72%) was prepared from 2, 2'-disulfanediylbis (N-phenylbenzamide) (0.46 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.16 g, yield 64%) was prepared from 2, 2'-disulfanediylbis (N- (4-methoxyphenyl) benzamide) (0.52 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.16 g, yield 57%) was prepared from 2, 2'-disulfanediylbis (N- (3-chloro-4-methoxyphenyl) benzamide) (0.58 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.15 g, yield 56%) was prepared from 2, 2'-disulfanediylbis (N- (4-isopropylphenyl) benzamide) (0.54 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.19 g, yield 70%) was prepared from 2, 2'-disulfanediylbis (N- (4-methoxybenzyl) benzamide) (0.52 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.15 g, yield 58%) was prepared from 2, 2'-disulfanediylbis (N- (3-ethylphenyl) benzamide) (0.51 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.18 g, yield 61%) was prepared from di-tert-butyl ( ( (2, 2'-disulfanediylbis (benzoyl) ) bis (azanediyl) ) bis (ethane-2, 1-diyl) ) dicarbamate (0.59 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol, ) according to the general preparation procedure described above.
  • This compound (0.08 g, yield 38%) was prepared from 2, 2'-disulfanediylbis (N- (2- (dimethylamino) ethyl) benzamide) (0.45 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.15 g, yield 55%) was prepared from 2, 2'-disulfanediylbis (N- (2-morpholinoethyl) benzamide) (0.53 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.17 g, yield 54%) was prepared from 2, 2'-disulfanediylbis (N- ( (4-fluorophenyl) sulfonyl) benzamide) (0.62 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.12 g, yield 51%) was prepared from 2, 2'-disulfanediylbis (N-cyclohexylbenzamide) (0.47 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.16 g, yield 49%) was prepared from 2, 2'-disulfanediylbis (N- ( [1, 1'-biphenyl] -4-ylmethyl) benzamide) (0.64 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.12 g, yield 61%) was prepared from 2, 2'-disulfanediylbis (N- (prop-2-yn-1-yl) benzamide) (0.38 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • This compound (0.12 g, yield 39%) was prepared from di-tert-butyl ( ( (2, 2'-disulfanediylbis (benzoyl) ) bis (azanediyl) ) bis (propane-3, 1-diyl) ) dicarbamate (0.62 g, 1 mmol) , DCM (20 mL) and liquid bromine (0.24 g, 1.5 mmol) according to the general preparation procedure described above.
  • the solid was dissolved in DCM and reacted with benzyl bromide (0.77 g, 4.5 mmol) in the presence of K 2 CO 3 (0.62g, 4.5 mmol) , Et 3 N (2.1g, 20.4 mmol) , and catalytic amount of KI at room temperature for overnight. The volatile was removed under reduced pressure. The crude residue was extracted with DCM and water. The organic phase was collected, dried over MgSO 4 and purified by flash chromatography to obtain the compound 5e (0.54 g, 2.23 mmol) .
  • E. coli TG1 was transformed with the IncX3 bla NDM-1 -bearing plasmid (similar as plasmid, pP855-NDM5, MF547508.1) originally isolated from a clinical K. Pneumoniae and was used in the preliminary MIC screening of test compounds alone and in combination with Meropenem.
  • Clinically isolated CRE strains shown in Table 2 were from our in-house bacterial strain library, which were isolated from different specimens (urine, faeces, and sputum) collected from patients in hospitals in Zhejiangzhou, China. 33
  • FIC index was calculated as FIC (compound) + FIC (Mem) , where FIC (compound) is the (MIC of compound in combination with Mem) / (MIC of compound alone) while FIC (Mem) is (MIC of compound in combination with Mem) / (MIC of Mem alone) .
  • FIC index of ⁇ 0.5 was deemed synergistic.
  • the bacterial suspension was injected into the hemocoels at the last left proleg of larvae.
  • Larvae were then treated with various treatments at 1 h before bacterial inoculation.
  • Treatments included vehicle, compound 11_a38 along, Mem along, compound 11_a38 in combination with Mem.
  • Treatments were performed in the same manner as infection, except that injections were into the next left proleg moving toward the head of the larvae.
  • Larvae were then incubated in Petri dishes at 37 °C and mortality rates were monitored at 12 h interval for 48 h. Larvae were considered dead if they did not respond to physical stimuli. Data were analyzed for statistical significance using a log-rank and ⁇ square test with 1 degree of freedom.
  • the purified NDM-1 protein was prepared as previously described. 32 Kinetic assay of NDM-1 was performed to determine the inactivation constants of compounds as previously described. 24 Briefly, followed by addition of 7 fold of Km of the reporter substrate nitrocefin, 1 nM of pure NDM-1 was mixed with different concentrations of compounds in 500 ⁇ L of 50 mM phosphate buffer with or without 50 ⁇ M ZnSO 4 . Bovine serum albumin (BSA) was then added to stabilize the activity of diluted NDM-1. The readout of the velocity can be recorded by the wavelength change at 482 nm. Independent assay was performed in triplicate.
  • BSA bovine serum albumin

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Abstract

L'invention concerne des compositions et des méthodes utiles dans le traitement de bactéries résistantes aux antibiotiques bêta-lactame.
PCT/CN2018/114268 2018-03-13 2018-11-07 Dérivés de 1,2-benzisosélénazol-3(2h)-one et de 1,2-benzisothiazol-3(2h)-one utilisés comme adjuvants d'antibiotiques bêta-lactame WO2019174279A1 (fr)

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WO2011116355A2 (fr) * 2010-03-19 2011-09-22 Sanford-Burnham Medical Research Institute Benzoisothiazolones en tant qu'inhibiteurs de phosphomannose isomérase (pmi)
US20140296310A1 (en) * 2011-08-16 2014-10-02 Georgetown University Methods of treating bacterial infections with 1,2-benzisothiazolinone and isoindolinone derivatives
WO2017091737A1 (fr) * 2015-11-25 2017-06-01 Molecular Defenses Corporation Formulations pharmaceutiques

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WO2011116355A2 (fr) * 2010-03-19 2011-09-22 Sanford-Burnham Medical Research Institute Benzoisothiazolones en tant qu'inhibiteurs de phosphomannose isomérase (pmi)
US20140296310A1 (en) * 2011-08-16 2014-10-02 Georgetown University Methods of treating bacterial infections with 1,2-benzisothiazolinone and isoindolinone derivatives
WO2017091737A1 (fr) * 2015-11-25 2017-06-01 Molecular Defenses Corporation Formulations pharmaceutiques

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JIN, W.B.: "Investigation of synergistic antimicrobial effects of the drug combinations of meropenem and 1, 2-benzisoselenazol-3(2H)-one derivatives on carbapenem-resistant Enterobacteriaceae producing NDM-1", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 155, 6 June 2018 (2018-06-06), pages 285 - 302, XP085431295, ISSN: 0223-5234, doi:10.1016/j.ejmech.2018.06.007 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112209899A (zh) * 2020-04-03 2021-01-12 华中师范大学 苯并硒唑酮类化合物及其应用和一种杀菌剂
CN112209899B (zh) * 2020-04-03 2023-03-10 华中师范大学 苯并硒唑酮类化合物及其应用和一种杀菌剂

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