NZ729460B2 - Methods for treating protozoan infections - Google Patents
Methods for treating protozoan infections Download PDFInfo
- Publication number
- NZ729460B2 NZ729460B2 NZ729460A NZ72946015A NZ729460B2 NZ 729460 B2 NZ729460 B2 NZ 729460B2 NZ 729460 A NZ729460 A NZ 729460A NZ 72946015 A NZ72946015 A NZ 72946015A NZ 729460 B2 NZ729460 B2 NZ 729460B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- formula
- compound
- bis
- dihydrazide hydrochloride
- eimeria
- Prior art date
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Abstract
The invention provides compounds of Formula (I), and their use in methods for treating or preventing a protozoan infection in a subject using a compound of Formula (I). The invention also provides the use of a compound of Formula (I) in the manufacture of a medicament for the treatment of a protozoan infection in a subject. The invention further provides a medical device when used in a method of treating or preventing a protozoan infection in a subject and to a medical device comprising the composition of the invention.
Description
METHODS FOR TREATING PROTOZOAN INFECTIONS TECHNICAL FIELD This invention relates to compounds of a | and their use in s for treating or preventing a protozoan infection in a subject using a compound of a I, the use of a compound of Formula | in the manufacture of a medicament for the treatment of a protozoan infection in a subject, and medical devices when used in a method of treating or preventing a oan infection in a subject.
BACKGROUND ART Giardiasis, amoebiasis and cryptosporidiosis are the most common protozoal parasitic diseases of the human intestinal tract and common causes of enteric disease in non—human animal species as well. Different drugs have been used for the management of these diseases, but many have a significant failure rate in ng parasites from the intestine and many are associated with a high incidence of undesirable side effects, which often leads to use being contraindicated in certain circumstances. There is a need in the art for an improved treatment which would require one or very few dosings, would be associated with a very high level of nce of the target protozoal agent, would kill intestinal cysts (to reduce environmental contamination and the reservoir of reinfection), be associated with no or only mild and well tolerated adverse effects, have no pre-existing resistance, be safe for use in pregnant and lactating humans and other species and/or be suitable for use as a preventive medication.
Many existing antiprotozoal , especially those for the treatment of giardiasis, have suboptimal intrinsic cy. For metronidazole giardia curative rates may be high, but have also been ed as low as 60% (measured by nce of the protozoan) in human adult and paediatric patients when it is administered for 5 - 10 days. Both idazole and tinidazole have been reported to have a median efficacy of approximately 89%. The newer antigiardial agent, nitazoxanide has demonstrated an overall response rate of 75% (measured by clearance of the protozoan), ranging between 64 and 94%.
To improve ance it is highly desirable that the dosage regimen is simple and of short on. As outlined above, the duration of dosing with metronidazole is most commonly -10 days, leaving many opportunities for missed treatments, poor compliance and reduced efficacy or ent failure.
Acquired resistance by giardia to the available treatments is widely experienced and an increasing cause of treatment failure. This is not surprising as the majority of currently recommended antiprotozoal agents have been in use for many decades. A review of antiprotozoal agents approved by the FDA between 1987 and 2013 (Kesselheim, A. S. and J. J.
Darrow (2014). "Drug Development and FDA Approval, 1938—2013." New England Journal of Medicine 370(26): e39) discloses only 7 new agents for all protozoan diseases (mefloquine in 1989, eflornithine in 1990, ntrine and uone in 1992, nitazoxanide in 2002, tinidazole in 2004 and the combination of ther and lumefantrine in 2009). Amongst these agents, only nitazoxanide and tinidazole are used for giardia treatment, and both have median efficacies less than 90%.
Frequently it is the profile of adverse effects that limits the use of antiprotozoal agents.
There is a ity of adverse effects of currently available antiprotozoal agents. For example, side effects for the widely used metronidazole e metallic taste, nausea, headache, vertigo, leukopaenia, insomnia and irritability. Less frequently, CNS toxicity has been reported especially with high doses, and alcohol ption is not recommended when taking metronidazole because of the possibility of developing a on similar to that of disulfiram. Metronidazole has been shown to be mutagenic in bacteria; based on animal studies, the drug has been carcinogenic at high doses and over long periods. For quinacrine adverse effects include headache, nausea, vomiting and a bitter taste, resulting in poor compliance. Yellow discolouration of the skin, urine and sclerae may also follow its administration. Blue or black tation of the nails, ria and exfoliative dermatitis can also occur. Other side effects reported are haemolysis in patients with ephosphate dehydrogenase (G6PD)— deficiency, toxic psychosis and exacerbation of psoriasis. Quinacrine, in common with other antiprotozoal agents, is able to cross the placenta and reach the foetus, contraindicating its use during pregnancy due to a possible link with birth deformities. Other serious side effects described have included psychiatric disturbances.
For the treatment of cryptosporidia and amoebiasis caused by Entamoeba histolytica the limitations on available treatments are even more limited than with giardia, with no consistently effective and specific treatment for cryptosporidia a, M. M. and A. C. White, Jr. (2010). "Treatment of sporidiosis: do we know what we think we know?" Curr Opin Infect Dis 23(5): 9).
There is an unmet Clinical need for antiprotozoan agents with novel mechanisms of action to supplement and/or replace currently available antiprotozoan agents, the efficacy of which is singly undermined by antiprotozoan resistance mechanisms. There additionally remains a need for alternative antiprotozoan agents in the treatment of infection by multi- resistant protozoa. However, as reported by the Pharmaceutical ch and Manufacturers of America in their 2013 report "Medicines in Development for Infectious Diseases" no novel antiprotozoan agents and few line ions are being developed that offer promising results over existing treatments.
It is an object of the present invention to overcome at least one of the failings of the prior The discussion of the background art set out above is intended to facilitate an tanding of the present invention only. The discussion is not an acknowledgement or admission that any of the material referred to is or was part of the common general knowledge as at the priority date of the application.
SUMMARY OF INVENTION According to one aspect of the invention, there is a method of treating or preventing a protozoan colonisation or infection in a subject, the method ing the step of stering a therapeutically effective amount of a compound of Formula | or stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof to the subject, wherein the protozoan infection is caused by a protozoan agent.
In one embodiment of the invention, the compound of a I, is: R1/ ,a’ A2 R3 \‘A’1 T Formulal In another embodiment of the invention, R1 is H, cycloalkyl, a II, or Formula III; R8\A,/A7 I? W Formula H a 111 In another embodiment of the invention, R3 is selected from the group consisting of : H; NH2; NHNHZO-CHz-CHg; NH-C(O)—phenyl; N-CH-chlorophenyl; NH-chlorophenyl; NH-CH2- phenyl; NH-N-CH-cycloalkyl; N and R4 is CH-N-CH-CCI- and R4 is bonded to R3; Formula IV; Formula V; and Formula VI; Formula IV Formula V Formula VI In r embodiment of the ion, A0 is N, C, CH, or A0 is C and A0 is bonded to R4 to form a triazole ring.
In another embodiment, R4 is CH-N-CH-CCI-. Preferably, R4 is bonded to R3 when Rsis In another embodiment of the invention, A1 is N, C, NH, -(CH)2-N-, -(C6H5)C-CH-N-, or Formula VII; C A22 A R \ / 23A / 25 N . ‘A24 H : I I A' ’A / 27 V 25 R28 \lAze R26 Formula VII In another embodiment of the invention, A2 is N, C, NH, N—C(O)—phenyl or Formula VII, or (CH2)n, wherein n is an integer between 1 and 3, inclusive.
In another embodiment of the invention, A3, A4, A5, A6, A7, A8, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21 A23, A24, A25, A26 and A27 are independently C, O, N, NH, S.
In another embodiment of the invention, A9 is C, O, N, NH, N-C(O)—O-CH2-CH3, N-C(O)— O-CH(CH3)2, N-C(O)—NH-CH2-CH3, N-C(O)—NH-CH2-phenyl, N-C(O)-CH2-CH2-CH2-CH2-CH2- CH3, N—C(O)—CH2—furan—2—yl.
In another ment of the invention, A10 is C, NH, —N-(CH)2-, -N-CH-C(CGH5)-.
In another embodiment of the invention, A22 is -CH(CH3)-, -N-CH-, -N-C(CH3)-, N- In r embodiment of the invention, R2 is H, COOH, CH2NH2, CHZOH, CHZNHNHZ, methyl, ethyl, , butyl, pentyl, heptyl, cyclopentyl, CH2(Cyclohexyl), (CH2)2(cyclopentyl), or Formula VII and R2 are R4 are bonded together to form a pyrimidine, ne or triazine ring, or R2 and R9 are bonded together to form a pyrrolidinyl oxindole ring.
In another embodiment of the invention, R4 is H2, N, NH, O, S, or R4 and A0 are bonded together to form a triazole ring, or R4 is N and R4 and R2 are bonded er to form a pyrimidine ring.
In another embodiment of the invention, R7 is H, Cl, Br, F, OH, CH3, OCH3, SCH3, CN, CCH, CF3, OCF3, SCF3, N02, butyl, t—butyl, dimethylamino, phenyl, n-propyl, i-propyl, -NH—C(O)— CH3, -(CH)2-COOH, piperazinyl, or R7 and R8 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, cyclic ring or benzene ring.
In another embodiment of the invention, R6, R8, R14, R16, R25 and R27 are independently H, OH, Cl, F, Br, CH3, CN, OCH3, COOH, N02, CF3, R8 and R7 bond together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring, or benzene ring, R14 and R15 are bonded together to form a substituted or tituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, R8 and R9 are bonded together to form a substituted or unsubstituted, saturated or rated aliphatic ring, heterocyclic ring or benzene ring, or R14 and R13 are bonded together to form a substituted or unsubstituted saturated or unsaturated aliphatic ring, cyclic ring or benzene ring.
In another embodiment of the invention, R5, R9, R17, R24 and R28 are independently H, O, OH, Cl, F, Br, NH2, CH3, CF3, OCH3, CN, N02, phenyl, -NH—CH(OH)—CH3, -NH-C(O)—CH3, or R9 and R8 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or e ring, or R13 and R14 are bonded together to form a substituted or unsubstituted saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring.
In another embodiment of the invention, R10, R11, R19, R20, R22 and R23 are independently H, Cl, or Br, or R10 and R11 are bonded er to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, cyclic ring or benzene ring, or R19 and R20 are bonded together to form a substituted or unsubstituted, saturated or unsaturated tic ring, heterocyclic ring or benzene ring, or R22 and R23 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, cyclic ring or benzene ring In another embodiment of the invention, R12, R18 and R21 are independently H, COOH, CH2NH2, CHZOH, methyl, ethyl, , butyl, entyl, or R12 and R13 are bonded together to form a pyrrolidinyl oxindole ring.
In another ment of the invention, R15 and R26 are independently H, Cl, Br, F, OH, CH3, OCH3, SCH3, CN, CF3, OCF3, SCFg, N02, CCH, n—butyl, l, dimethylamino, phenyl, n- propyl, yl, -NH-C(O)—CH3, -(CH)2-COOH, piperazinyl, or R15 and R14 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, and In another embodiment of the invention, ----" is a double bond or a single bond.
In another embodiment of the invention, the compound of Formula I, or a stereoisomer, tautomer, ceutically acceptable salt, or prodrug thereof, is selected from the compounds ted in Figure 1.
In another embodiment of the invention, the compound of Formula I, or a stereoisomer, tautomer, pharmaceutically able salt, or prodrug f comprises the following features: wherein A0 is C; wherein A1 is N; or Formula Vll; wherein A2 is N; or NH; wherein A3, A4, A6, A7, A11, A12, A14, A15, are N; or C; wherein A5, A13, A23, A24, A25, A26 and A27 are C; wherein A8 and A21 are 8; wherein A9 is NH; wherein A10 is N; n A22 is —N-CH-; -N-C(CH3)-; or —N-C(CHZOH)—; wherein R1 is H; Formula II; Formula Ill; cycloalkyl; wherein R2 is H; methyl; ethyl; CH2NHNH2; CHZOH; butyl; cyclopentyl; or Formula VII and R2 is bonded to R4, to form a pyrimidine ring; wherein R3 is NH2; Formula IV; Formula V; Formula VI; NH2, NH-N-CH-cycloalkyl; or O- CHz-CH3; wherein R4 is NH; O; S; or R4 is N and R4 and R2 are bonded together to form a pyrimidine ring; wherein R7 is H; F; Cl; CF3; methyl; R7 and R8 are bonded together to form an unsubstituted, benzene ring; OH; l; ; dimethylamino; i-propyl; n-propyl; CN; CCH; n-butyl; SCH3; R7 and R8 are bonded together to form an unsubstituted, unsaturated heterocyclic ring; OCH3; Br; OCFg; piperazin—1-yl; or SCFg; wherein R6, R8, R14, and R16 are independently H; OH; F; OCH3; CF3; methyl; CI; CN; Br; R8 and R7 are bonded together to form an unsubstituted, benzene ring; R8 and R7 are bonded together to form an unsubstituted, unsaturated heterocyclic ring; R14 and R15 are bonded together to form an unsubstituted, benzene ring; or R14 and R15 are bonded together to form an unsubstituted, rated heterocyclic ring; wherein R5, R9, R13, and R17 are ndently H; OH; NHZ; CI; F; OCH3; OH; -NH- CH(OH)—CH3; wherein R12 is H; methyl; ethyl; CHZOH; or cyclopentyl; wherein R15 is H; F; CI; CF3; methyl; R7 and R8 are bonded together to form an unsubstituted, benzene ring; OH; t—butyl; phenyl; dimethylamino; i—propyl; n-propyl; CN; CCH; n-butyl; SCH3; R15 and R14 are bonded together to form an unsubstituted, unsaturated heterocyclic ring; OCH3; Br; OCF3; piperazinyl; or SCF3; wherein R24 and R28 are independently H; OH; or Cl; wherein R25 and R27 are independently H; or OH; wherein R26 is H; CH3; Br; CI; OH; dimethylamino; -O-P(O)(OEt)2; CF3; or F; and wherein "----" is ndently a single or a double bond.
In another embodiment of the invention, the compound is ed from the group comprising: ; NCL009; NCL023; NCL025; NCL026; NCL028; NCL029; ; NCL037; NCL039; NCL040; NCL050; ; NCL062; ; NCL065; NCL068; NCL075; NCL076; NCL078; NCL079; NCL080; NCL081; NCL084; NCL085; NCL086; NCL088; NCL089; NCL090; NCL092; NCL094; NCL095; NCL097; NCL098; NCL099; NCL101; NCL104; NCL105; NCL106; NCL108; NCL111; NCL112; NCL114; NCL115; NCL116; NCL118; NCL119; NCL121; NCL122; NCL123; ; NCL125; NCL126; NCL130; NCL131; NCL132; NCL133; NCL135; NCL136; NCL137; NCL138; NCL139; NCL140; NCL141; NCL144; ; NCL146; NCL147; NCL148; NCL150; NCL152; NCL153; NCL154; NCL156; NCL157; NCL158; ; NCL161; NCL162; NCL164; NCL165; NCL166; NCL167; NCL168; NCL169; NCL170; NCL171; NCL172; NCL173; NCL174; NCL176; NCL177; NCL178; ; NCL180; NCL181; NCL183; NCL184; NCL185; NCL186; NCL187; ; ; NCL190; NCL193; NCL194; NCL195; NCL196; NCL197; NCL198; NCL199; NCL200; NCL201; ; NCL203; ; NCL205; NCL206; NCL207; NCL208; NCL209; NCL210; NCL211; NCL212; NCL213; NCL215; NCL216; NCL217; NCL218; NCL219; NCL220; NCL221; NCL222; NCL223; NCL223; NCL224; NCL225; NCL226; NCL227; NCL228; NCL229; NCL230; NCL231; ; ; NCL234; ; NCL236; NCL237; NCL238; NCL239; NCL240; NCL241; NCL242; NCL243; NCL244; NCL245; NCL246; NCL247; NCL248; NCL249; NCL250; NCL251; NCL252; NCL253; ; NCL255; NCL256; NCL257; NCL258; NCL259; NCL260; NCL261; NCL262; NCL263; ; NCL265; NCL266; NCL267; NCL268; NCL269; NCL270; NCL271; NCL272; ; NCL274; and NCL275.
In another embodiment of the invention, the compound is selected from the group comprising: NCL028; ; NCL062; NCL078; NCL079; NCL080; NCL081; NCL084; NCL088; NCL089; NCL097; ; ; NCL146; NCL157; NCL158; NCL177; NCL179; NCL188; NCL193; NCL195; NCL196; NCL197; NCL199; ; NCL204; NCL205; NCL215; ; NCL217; NCL219; NCL221; NCL245 and NCL246.
In a preferred embodiment of the invention, the compound is selected from the group comprising: NCLO62; NCLO78; NCL079; NCL080; NCL081; NCL084; NCL089; NCL097; NCL099; NCL157; ; NCL179; NCL188; ; NCL195; NCL196; ; NCL204; NCL216; ; NCL219; NCL221; NCL245 and NCL246.
In an even more preferred embodiment of the invention, the compound is selected from the group comprising: NCLO62; NCL089; NCL097; NCL099; NCL157; ; NCL188; NCL193; NCL195; NCL196; NCL216; NCL219; and NCL221.
In an even more preferred embodiment of the invention, the compound is selected from the group comprising: NCLO62; NCL097; NCL099; NCL157; NCL179; ; NCL195; and NCL196.
In another embodiment of the invention, the compound is a chloride salt.
In another embodiment of the invention, the compound is a compound ed from the group comprising: NCL812 and NCL062. In another embodiment of the invention, the compound is not a compound selected from the group sing: NCL812 and NCL062. For e, the compound is NCL099.
In another embodiment of the invention, the compound is a compound selected from the group comprising: NCL020, NCL021, NCL024, NCL035, NCL072, NCL077, NCL107, NCL109, NCL134, NCL143, NCL143, NCL151, NCL155 and . In another embodiment of the invention, the compound is not a compound selected from the group comprising: NCL020, NCL021, NCL024, NCL035, , NCL077, NCL107, , NCL134, NCL143, NCL143, NCL151, NCL155 and NCL160. For e, the nd is NCL099.
In another embodiment of the ion, the subject is an animal most preferably selected from the group comprising: human, canine, feline, bovine, ovine, e, porcine, avian, piscine and equine species.
In another embodiment of the invention, the compound is administered to the subject in a dose in the range of 0.1 mg/kg to 250 mg/kg bodyweight.
In another embodiment of the ion, the protozoan agent is selected from the group of protozoa genera comprising: Acanthamoeba, Babesia, Balamuthia, Balantidium, Besnoitia , Blastocystis, Chilomastix, Cochlosoma, Cryptosporidium, Cyclospora, Cystoisospora, Cytauxzoon, Dientamoeba, Eimeria, Endolimax, Entamoeba, Giardia, Haemoproteus, dia Hartmannella, Hepatozoon, Hexamita, Histomonas, lsospora, Leishmania (including subgenus Viannia), Leucocytozoon, ria, Neospora , Pentatrichomonas, dium (including era Plasmodium (Bennettinia) (birds); Plasmodium (Giovannolaia) (birds); Plasmodium (Haemamoeba) (birds); Plasmodium (Huffia) (birds); Plasmodium (Laverania) (higher primates, includes Plasmodium falciparum); Plasmodium (Novyella) (birds); Plasmodium (Paraplasmodium) (lizards); dium (Plasmodium) (higher primates, includes Plasmodium brasilianum, cynomolgi, inui, si, malariae]; Plasmodium (Sauramoeba) (lizards); Plasmodium (Vinckeia)), Sappinia, Sarcocystis, Tetratrichomonas, Theileria, Toxoplasma, Trichomonas, Tritrichomonas, Trypanosoma (Subgenera Duttonella, Herpetosoma, Nannomonas, Schizotrypanum, Trypanozoon), Tyzzeria and Wenyonella.
In another embodiment of the invention, the protozoan agent is selected from the group of protozoa listed in Table 1 (see below).
In another embodiment of the invention, the protozoan agent is a resistant oa.
In another embodiment of the invention, the infection or colonisation is caused by a mixture of at least two protozoan agents.
In another embodiment of the invention, the protozoan agent is resistant to one or more compounds ed from the group listed in Table 2 (see below).
In r embodiment of the invention, the protozoan agent is resistant to the compound when the protozoan agent is exposed to the compound at a concentration range selected from the following: 0.001 ug/mL - 10,000 ug/mL; 0.01 ug/mL - 1000 ug/mL; 0.10 ug/mL - 100 ug/mL; and 1 ug/mL - 50 ug/mL.
In another embodiment of the invention, the protozoan infection or colonisation in the subject is a zoonosis.
In another embodiment of the invention, the protozoan infection or sation in the t substantially causes an indication selected from the group sing: Trypanosomosis (caused by the order, Kinestoplastorida of the family, Trypanosamidae); Amboebiasis (caused by the subphylum, Sarcodina, of the order, Amoebidorida, of the family Endamoebidae); Babesiosis (caused by the class, Piroplasmida, of the family, Babesiidae); Balantidiosis (caused by the phylum, Ciliphora, of the order, stomatorida, of the family Balantidiidae); Chagas Disease (caused by the order, Kinestoplastorida, of the family, Trypanosomatidae); Cryptosporidiosis (caused by the subclass, Coccidea, of the family, Cryptosporidiidae); osis (caused by the class, tigophora, of the order, Diplomonadida, of the , Diplomonadida, including Giardia lamblia); Leishmaniasis (caused by the class, Zoomastigophora, of the family, Trypanosomatidae, of the genus, Leishmania); Malaria (caused by the genus, Plasmodium, including P. arum, P. vivax, P. ovale, and P. malariae) Sarcocystosis (caused by the subclass, Coccidia, of the order Eucoccidiorida, of the family Sarcocystidae); Toxoplasmosis (cause by the subclass, Coccidia, of the order, Eucoccidiorida, of the , Sarcocystidae, including Toxoplasma gondii); Cyclosporiasis (caused by the species, Cyclospora cayetanensis); Infections caused by free-living Amoebae (caused by Naegleria, Acanthamoeba and/or Balamuthia); Malaria in Non-human es (caused by the genus, Plasmodium); Microsporidiosis (caused by Enterocytozzon bieneusi, Encephalitizoon intestinalis and/or E. cuniculi); Atypical Human Trypanosomosis (T. lewisi, T. evansi, T. brucei, T. vivax, and/or T. ense); Trichomoniasis (caused by Trichomonas vaginalis); Amoebic dysentery (caused by Entamoeba histolyticum); and Acanthamoebiasis (caused by Acanthamoeba).
In another embodiment of the invention, the therapeutically effective amount of compound of Formula I, or a therapeutically acceptable salt thereof, is stered to the subject by oral administration.
In another embodiment of the invention, the therapeutically effective amount of nd of Formula I, or a therapeutically acceptable salt thereof, is administered to the t together with a second antimicrobial agent selected from the group consisting of compounds listed in Table 2 (see below).
In another embodiment of the invention, the therapeutically effective amount of compound of Formula I, or a eutically acceptable salt thereof, is administered to the subject by parenteral administration.
In another ment of the invention, the therapeutically effective amount of compound of Formula I, or a eutically acceptable salt thereof, is administered to the subject by topical administration.
In a r aspect of the invention, the invention is a antiprotozoan pharmaceutical composition comprising a therapeutically ive amount of a compound of Formula I, or a therapeutically acceptable salt thereof, and optionally a pharmaceutically able excipient or carrier.
In a further aspect of the invention, the invention is a antiprotozoan veterinary composition comprising a therapeutically ive amount of a compound of Formula |, or a therapeutically acceptable salt thereof, and optionally a veterinary acceptable excipient or carrier.
In another embodiment of the invention, the composition ses a further crobial agent selected from the group listed in Table 2 (see below).
In another embodiment of the invention, the composition is adapted for oral administration.
In another embodiment of the invention, the composition is adapted for parenteral administration.
In another embodiment of the invention, the composition is adapted for topical administration.
In a further aspect of the invention, the invention is the use of a compound of Formula I, or a therapeutically able salt thereof, in the manufacture of a medicament for the treatment of a protozoan colonisation or ion in a subject. In another embodiment of the invention, the use comprises administering a therapeutically ive amount of compound of Formula I, or a therapeutically acceptable salt thereof, to the subject. In another embodiment of the invention, the compound of Formula | is stered to the subject in a dose in the range of 0.1 mg/kg to 250 mg/kg body weight. In one preferred embodiment, the compound is administered to the subject in a dose in the range selected from the group consisting of: 0.1 mg/kg to 100 mg/kg body ; 0.1 mg/kg to 50 mg/kg body weight; 1 mg/kg to 20 mg/kg body weight; 1 mg/kg to 10 mg/kg body weight; and 2 mg/kg to 5 mg/kg body weight. In one red embodiment, the compound is administsred to the subject at a dose that achieves within 1 hour a compound plasma concentration range ed from the group consisting of: 0.01ug/ml - 100ug/ml; 0.1ug/ml - 10ug/ml; 1ug/ml - 8ug/ml. Preferably, after 1 hour, the dose achieves a compound plasma concentration above 8ug/ml. Preferably, after 7 hours, the dose es a compound plasma concentration above 8ug/ml. Preferably, after 24 hours, the dose achieves a compound plasma concentration above 8ug/ml.
In one preferred embodiment, the compound is administered to the subject at a frequency selected from the group consisting of: every 30 minutes; every hour; every 2 hours; every 3 hours; every 4 hours; every 5 hours; every 6 hours; every 8 hours; every 12 hours; once daily; every 2 days; once weekly; twice weekly; once every 2 weeks; once monthly; once every 2 months; once every 3 months; once every 4 ; once every 5 months; once every 6 months; once every year; once every 2 years; and once.
In another embodiment of the invention, the medicament is administered to the subject by oral administration. In another embodiment of the invention, the medicament is administered to the subject by parenteral administration. In another ment of the ion, the medicament is administered to the subject by topical administration.
In a further aspect of the invention, the ion is a medical device when used in a method of ng or preventing a protozoan sation or infection in the subject, wherein the l device comprises the composition of the invention. In another embodiment of the invention, the medical device is in a form selected from the group comprising: a plaster, a bandage, a dressing or implant applied to a protozoan colonisation or infection in a subject.
In a further aspect of the invention, the ion is a method of killing protozoa, the method including the step of contacting the protozoa with a compound of Formula I, or a therapeutically acceptable salt thereof.
In a r aspect of the invention, the invention is the use of a compound of Formula |, or a eutically acceptable salt thereof, to kill protozoa, said use comprising the step of contacting the oa with a compound of Formula I, or a therapeutically acceptable salt thereof.
In a further aspect of the invention, the invention is a , a composition, device or a use, substantially as described herein with reference to the accompanying Examples and Figures.
In a preferred aspect of the invention, the compound of a | is robenidine (also referenced in this specification as NCL812 and also known as 1,3-bis[(E)—(4- ch|oropheny|)methyleneamino]guanidine), which has a structure as follows: In one preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or g thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A5, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R7, R9, R12, R13, R15, R16, R17 are H; R4 is 0; R8 and R14 are CF3; and "-—-—" in Formula I between A0 and A1, all Formula II and all Formula IV "—--—" are double bonds. An example of a compound of this embodiment of the invention includes (NCL101): In another preferred embodiment of the ion, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is NH2; A1 is N and A2 is NH; A0, A3, A4, A5, A6, and A7 are C; R2, R5, R6, R7, and R8 are H; R4 is NH; R9 is CI; and "-——-" in Formula | between A0 and A1 and all Formula II "---- are double bonds. An e of a compound of this embodiment of the invention includes (NCL015): In another preferred ment of the invention, the compound is a nd of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16, R17 are H; R4 is NH; R7 and R15 are F; and "----" in Formula I n A0 and A1, all Formula II and all Formula IV "—-— -" are double bonds. An example of a compound of this embodiment of the invention includes (NCL021): In another red embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is a IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R7, R9, R12, R13, R15, R16, R17 are H; R4 is NH; R8 and R14 are F; and "----" in Formula I between A0 and A1, all Formula II and all Formula IV "--- -" are double bonds. An example of a compound of this embodiment of the invention includes (NCL023): In another preferred embodiment of the invention, the compound is a nd of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is a IV A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R7, R8, R12, R14, R15, R16, R17 are H; R4 is NH; R9 and R13 are OCH3; and "—---" in Formula I between A0 and A1, all Formula II and all Formula IV "- -—-" are double bonds. An e of a compound of this embodiment of the invention includes (NCL028): In another preferred embodiment of the ion, the compound is a nd of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R7, R9, R12, R13, R15, R16, R17 are H; R4 is NH; R8 and R14 are OCH3; and "----" in Formula I between A0 and A1, all Formula II and all Formula IV "-—--" are double bonds. An example of a compound of this embodiment of the invention includes (NCL029): o \H H/ ’Y\N/\©/\oNH In another preferred embodiment of the ion, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is NH2; A1 is N; A2 is NH; A0, A3, A4, A5, A5, and A7 are C; R2, R5, R6, R8 and R9 are H; R4 is NH; R7 is CI; and "--—-" in Formula I between A0 and A1, and all a II —--- are double bonds. An example of a compound of this embodiment of the invention includes (NCL030): In another preferred embodiment of the invention, the compound is a compound of a I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16, R17 are H; R4 is NH; R7 and R15 are CF3; and "----" in Formula | between A0 and A1, aII Formula II and Formula IV "---- are double bonds. An example of a nd of this embodiment of the invention includes (NCL035): In another red embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16, R17 are H; R4 is NH; R7 and R15 are methyl; and "--—-" in Formula | between A0 and A1, a" Formula II and Formula IV "----" are double bonds. An example of a nd of this embodiment of the invention includes (NCL038): In another preferred embodiment of the ion, the compound is a nd of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R5, R7, R8, R12, R14, R15, R16, R17 are H; R4 is NH; R9 and R13 are methyl; and "--—-" in Formula I between A0 and A1, aII Formula II and a IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL039): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or g thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R5, R7, R9, R12, R13, R15, R16 and R17 are H; R4 is NH; R3 and R14 are methyl; and "----" in Formula I between A0 and A1, aII Formula II and Formula IV "--—-" are double bonds. An example of a compound of this embodiment of the invention includes (NCL040): In another preferred embodiment of the invention, the nd is a compound of Formula I, or a isomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is a II; R3 is NHZ; A1 is N; A2 is NH; A0, A3, A4, A5, A5, and A7 are C; R2, R5, R6, R8, and R9 are H; R4 is NH; R7 is CF3; and "--—-" in Formula | between A0 and A1, and a" Formula || "--—-" are double bonds. An example of a compound of this embodiment of the invention includes (NCL041): In another red embodiment of the invention, the compound is a compound of a I, or a stereoisomer, er, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is NH2; A1 is N; A2 is NH; A0, A3, A4, A5, A5, and A7 are C; R2, R5, R6, R7, and R9 are H; R4 is NH; R8 is CF3; and "—--—" in Formula | between A0 and A1, and all Formula II "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL043): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically able salt, or prodrug thereof, wherein R1 is Formula II; R3 is NH2; A1 is N; A2 is NH; A0, A3, A4, A5, A6, and A7 are C; R2, R5, R6, R8, and R9 are H; R4 is NH; R7 is methyl; and "—---" in Formula I between A0 and A1, and all Formula II "---- are double bonds. An e of a nd of this embodiment of the invention includes(NCL044): In r preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is NH2; A1 is N; A2 is NH; A0, A3, A4, A5, A5, and A7 are C; R2, R5, R6, R7, and R9 are H; R4 is NH; R8 is CI; and "—-—-" in Formula | between A0 and A1, and all Formula II "----" are double bonds. An example of a compound of this embodiment of the ion includes (NCL052): In another preferred embodiment of the invention, the compound is a nd of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R7, R9, R12, R13, R15, R16, R17 are H; R4 is NH; R8 and R14 are CI; and "—---" in Formula | between A0 and A1, all Formula II and Formula IV "--—-" are double bonds. An example of a compound of this embodiment of the invention includes (NCL054): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, n R1 is Formula II; R3 is a IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2 and R12 are ; R5, R5, R8, R9, R13, R14, R16, R17 are H; R4 is NH; R7 and R15 are CF3; and "----" in Formula I between A0 and A1, aII Formula II and a IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL061): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is a II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2 and R12 are methyl; R5, R5, R8, R9, R13, R14, R16 and R17 are H; R4 is NH; R7 and R15 are CI; and "--—-" in Formula | between A0 and A1, a" Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL062): Cl HCI Cl In r preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically able salt, or prodrug thereof, n R1 is Formula II; R3 is NHNH2; A1 is N; A2 is NH; A0, A3, A4, A5, A6, and A7 are C; R2 is methyl, R5, R6, R8 and R9 are H; R4 is NH; R7 is Cl; and "----" in Formula | between A0 and A1, and all Formula II "----" are double bonds. An example of a compound of this embodiment of the invention es (NCL069): \ H H N’ T ‘NHZ Cl HCI In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R7, R9, R12, R13, R15, R16, and R17 are H; R4 is S; Re and R14 are Cl; and "-—--" in Formula | between A0 and A1, all a II and Formula IV "—- --" are double bonds. An example of a nd of this embodiment of the invention includes (NCL070): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is a II; R3 is NHZ; A1 is N;A2 is NH; A0, A3, A4, A5, A5, and A7 are C; R2, R5, R6, R8, and R9 are H; R4 is NH; R7 is Cl; and "—-—-" in Formula | n A0 and A1, and all Formula II "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL072): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug f, wherein R1 is Formula II; R3 is NHNH2; A1 is N; A2 is NH; A0, A3, A4, A5, A6, and A7 are C; R2 is methyl; R5, R6, R8, and R9 are H; R4 is NH; R7 is CF3; and "-—--" in Formula | n A0 and A1, and all Formula II "--—-" are double bonds. An example of a compound of this embodiment of the invention includes (NCL073): In another preferred ment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, and R16 are H; R4 is NH; R7_ R15 and R17 are CI; and "-—--" in Formula | between A0 and A1, all Formula II and a IV "----" are double bonds. An example of a compound of this embodiment of the ion includes (NCL074): In another preferred embodiment of the invention, the compound is a compound of a I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, and R16 are H; R4 is NH; R7 is CI; R15 is CF3; R17 is F; and "---- in Formula | between A0 and A1, aII Formula II and Formula IV "--—-" are double bonds. An example of a compound of this ment of the invention includes (NCL078): In another preferred embodiment of the invention, the compound is a nd of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16 and R17 are H; R4 is NH; R7is CI; R15 is F; and "----" in Formula | n A0 and A1, aII Formula II and Formula IV "-- -—" are double bonds. An example of a compound of this embodiment of the invention es (NCL079): \ H H U" f "U/NH Cl F In another preferred embodiment of the invention, the compound is a compound of Formula I, or a isomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is a IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R13, R14, R16 and R17 are H; R4 is NH; R7 is CI; R12 is methyl; R15 is CF3; and "----" in Formula | between A0 and A1, a|| Formula II and a IV "—-—- a are double bonds. An example of a compound of this embodiment of the invention includes (NCL080): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, er, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is a IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R13, R14, R16 and R17 are H; R4 is NH; R7 and R15 are Cl; R12 is methyl; and "----" in Formula | A0 and A1, a|| Formula II and Formula IV "—--—" are double bonds. An e of a compound of this embodiment of the invention includes H H \ / Clon ,, CI In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, er, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R5, R8, R9, R12, R13, R14, R15, and R16 are H; R4 is NH; R7 and R17 are CI; and "-—--" in Formula I between A0 and A1, aII Formula II and Formula IV "- ---" are double bonds. An example of a compound of this embodiment of the invention includes (NCL082): \ H H Q‘N’ / 7F ‘N/D CI Cl In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically able salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, and R16 are H; R4 is NH; R7 and R15 are Cl; R17 is F; and "----" in Formula | between A0 and A1, all Formula II and Formula IV "-—-- are double bonds. An e of a compound of this embodiment of the invention includes (NCL084): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is a IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R5, R8, R9, R12, R13, R15, R16, and R17 are H; R4 is NH; R7is CI; R14 is ON; and "----" in Formula I between A0 and A1, aII Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL086): H H In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically able salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R15, and R16 are H; R4 is NH; R7iS CI; R17 is F; and "---—" in a | n A0 and A1, all a II and a IV "—- --" are double bonds. An example of a compound of this embodiment of the invention includes (NCL088): In another preferred ment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is a II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2 and R12 are methyl; R5, R6, R8, R9, R13, R14, R16, and R17 are H; R4 is NH; R7is Cl; R15 is CF3; and "----" in Formula | between A0 and A1, all a II and Formula IV "—--—" are double bonds. An example of a compound of this embodiment of the invention includes 9): \ H H / z \ In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is a IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R9, R12, R13, R16, and R17 are H; R4 is NH; R7 and R3 are bonded together to form an unsubstituted, benzene ring; R14 and R15 are bonded together to form an unsubstituted, benzene ring; and "---—" in Formula | between A0 and A1, all Formula II and Formula IV "---- are double bonds. An example of a compound of this embodiment of the invention includes (NCL093): H H 00W 00NH In another preferred embodiment of the invention, the compound is a nd of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein A0 is C; A1 is N; A2 is NH; R1 is cyclohexyl; R3 is H-cyclohexyl; R4 is NH; R2 is H; and "---—" in Formula I between A0 and A1 is a double bond. An example of a compound of this embodiment of the invention includes (NCL094): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically able salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, , A12, A13, A14 and A15, are C; R2, R5, R9, R12, R13 and R17 are H; R4 is NH; R6, R7, R8, R14, R15, and R16 are OH; and "—-—-" in Formula | between A0 and A1, all Formula II and Formula lV "-— --" are double bonds. An example of a compound of this ment of the invention includes (NCL097): ] In another preferred ment of the invention, the compound is a compound of Formula I, or a isomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R5, R8, R9, R12, R13, R14, R16 and R17 are H; R4 is NH; R7 and R15 are t—butyl; and "----" in Formula | between A0 and A1, all Formula II and Formula IV "-—--" are double bonds. An example of a compound of this embodiment of the invention includes (NCL099): In r preferred embodiment of the ion, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R7, R8, R9, R12, R13, R14, and R15 are H; R4 is NH; R5, R6, R15, and R17 are OH; and "—--—" in Formula | between A0 and A1, all Formula II and Formula IV "—--—" are double bonds. An example of a compound of this embodiment of the invention includes (NCL101): In r preferred embodiment of the invention, the nd is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R3, R12, R14, and R17 are H; R4 is NH; R6, R7, R9, R13, R15, and R16 are OH; and "----" in a | n A0 and A1, all Formula II and Formula IV "-—--" are double bonds. An example of a compound of this embodiment of the invention includes (NCL104): OH OH \ H H / N’ T ‘N HO OH OH HCI OH In r preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R12, R16, and R17 are H; R4 is NH; R7, R8, R9, R13, R14, and R15 are OH; and "—-——" in Formula I between A0 and A1, all Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL097): ] In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug f, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R6, R7, R8, R9, R12, R13, R14, R15, and R16 are H; R4 is NH; R5 and R17 are OH; and "--—-" in Formula I between A0 and A1, all Formula II and Formula IV "-—--" are double bonds. An e of a compound of this embodiment of the invention includes (NCL107): In another preferred embodiment of the ion, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R7, R8, R9, R12, R13, R14, R15, and R17 are H; R4 is NH; R6 and R15 are OH; and "--—-" in Formula | between A0 and A1, all Formula II and Formula IV "-—--" are double bonds. An example of a compound of this embodiment of the invention includes (NCL108): \ H H / N’ Y ‘N OH OH In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R8, R9, R12, R13, R14, and R17 are H; R4 is NH; R6, R7, R15, and R16 are OH; and "----" in a I between A0 and A1, all Formula II and Formula IV "-—--" are double bonds. An example of a compound of this embodiment of the ion includes (NCL111): In another preferred embodiment of the invention, the compound is a compound of Formula |, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, n R1 is Formula II; R3 is a IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16, and R17 are H; R4 is NH; R7 and R15 are ; and "----" in Formula | between A0 and A1, all Formula II and Formula IV "--—-" are double bonds. An example of a compound of this embodiment of the invention includes (NCL112): \ H H / N’ 71/ \N O 0 In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug f, wherein R1 is a II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16, and R17 are H; R4 is NH; R7 and R15 are dimethylamino; and "----" in Formula | between A0 and A1, all Formula II and Formula IV "--—-" are double bonds. An example of a compound of this ment of the invention es (NCL113): H H \ afI;NH / T HCI T In another red ment of the invention, the compound is a compound of a I, or a stereoisomer, tautomer, ceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R3, R9, R12, R13, R14, and R17 are H; R4 is NH; R6 and R16 are OCH3; R7 and R15 are OH; and "----" in Formula I between A0 and A1, all Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL117): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug f, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16, and R17 are H; R4 is NH; R7 and R15 are i-propyl; and "—-—-" in Formula I between A0 and A1, all Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL120): In another preferred embodiment of the invention, the compound is a nd of Formula I, or a stereoisomer, tautomer, ceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16, and R17 are H; R4 is NH; R7 and R15 are n-propyl; and "---— in Formula I between A0 and A1, a" Formula II and Formula IV "---— u are double bonds. An example of a compound of this embodiment of the invention includes (NCL121): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically able salt, or g thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R8, R9, R12, R13, R14, and R17 are H; R4 is NH; R6, R7, R15, and R16 are F; and "----" in Formula | between A0 and A1, all Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL123): ] In another preferred embodiment of the invention, the compound is a nd of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16, and R17 are H; R4 is NH; R7 and R15 are CCH; and "—-—-" in Formula | between A0 and A1, all Formula II and Formula IV "----" are double bonds. An example of a compound of this ment of the invention includes (NCL126): In another red embodiment of the invention, the compound is a compound of Formula I, or a isomer, er, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R7, R8, R9, R12, R13, R14, R15, and R17 are H; R4 is NH; R6 and R16 are Br; and "--—-" in Formula | between A0 and A1, all Formula II and Formula lV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL131): In r preferred ment of the invention, the compound is a compound of a I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16, and R17 are H; R4 is NH; R7 and R15 are butyl; and "—---" in Formula | between A0 and A1, all Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL136): In another preferred ment of the invention, the compound is a nd of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, n R1 is Formula II; R3 is Formula IV; A1 is -C(C6H5)-CH-N- and A10 is -N-CH-C(C6H5)-; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R6, R7, R8, R9, R12, R13, R14, R15, R16, and R17 are H; R4 is NH; and "--—-" in Formula | between A0 and A1, all Formula II and Formula IV "---- are double bonds. An example of a nd of this embodiment of the invention includes (NCL138): H H NTNN/ In another preferred ment of the invention, the compound is a compound of Formula |, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16, and R17 are H; R4 is NH; R7 and R15 are CH38; and "--—-" in Formula | between A0 and A1, all Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL140): In another preferred embodiment of the ion, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula III; R3 is Formula VI; A0 is C; R2 and R21 are H; A1 and A20 are N; A2 and A19 are NH; A8 and A21 are 8; R4 is NH; R10 and R11 are bonded er to form a substituted benzene ring; R22 and R23 are bonded together to form a substituted e ring; and "----" in Formula | between A0 and A1, and all a III and Formula VI "-—--" are double bonds. An example of a compound of this embodiment of the invention includes (NCL141): CI CI \ H n / N' ‘N I Y \ 3 NH 3 ] In another preferred embodiment of the invention, the nd is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2 and R12 are ; R5, R6, R7, R8, R9, R13, R14, R15, R16, and R17 are H; R4 is NH; and "-—--" in Formula I between A0 and A1, all Formula II and Formula IV "--—-" are double bonds. An example of a compound of this ment of the invention includes (NCL143): \ H H / N’ W ‘N NH.HC| In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is a II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R9, R12, R13, R16, and R17 are H; R4 is NH; R7 and R8 are bonded together to form an unsubstituted, heterocyclic ring; R14 and R15 are bonded together to form an unsubstituted, unsaturated heterocyclic ring; and "----" in Formula I between A0 and A1, a|| Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL146): \ H H / / N" Y ‘N \ NH.HCI N N H H In another preferred embodiment of the invention, the compound is a nd of a I, or a stereoisomer, tautomer, ceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 is -(CH)2-N- and A10 is —N-(CH)2-; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 arid A15, are C; R2, R5, R6, R8, R9, R12, R13, R14. R16, and R17 are H; R4 is NH; R7 and R15 are OCH3; and "—-—-" in Formula | between A0 and A1, all Formula II and Formula IV "---- are double bonds. An e of a compound of this embodiment of the invention includes (NCL150): WM, TWmNH.HCI\ N N / \O 0/ In another preferred ment of the invention, the compound is a compound of Formula |, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is a II; R3 is a IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16, and R17 are H; R4 is NH; R7 and R15 are OH; and "----" in Formula | between A0 and A1, all Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL151): ?N’ Y ‘N/\©\NH.HCI HO OH In another preferred embodiment of the invention, the compound is a compound of Formula |, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug f, wherein R1 is Formula II; R3 is Formula lV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2 and R12 are ethyl; R5, R6, R8, R9, R13, R14, R16, and R17 are H; R4 is NH; R7 and R15 are Cl; and "-—-—" in Formula | between A0 and A1, all Formula II and Formula lV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL153): Cl CI In another preferred embodiment of the invention, the compound is a compound of a I, or a stereoisomer, tautomer, pharmaceutically able salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and Ag are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2 and R12 are methyl; R5, R6, R8, R9, R13, R14, R16, and R17 are H; R4 is NH; R7 and R15 are Br; and "---—" in Formula | between A0 and A1, all Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL155): \ H H / N’ W ‘N NH.HCI Br Br In another red ment of the invention, the compound is a compound of a I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or g f, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and Ag are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R12, R14, R16, and R17 are H; R4 is NH; R7 and R15 are Cl; R9 and R13 are NH2; and "-—--" in Formula | between A0 and A1, all Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the invention includes (NCL157): L H H a». N, N, xix {W wt r t J Cl / "~42 \'-~,J'//'I ECI In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and Ag are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2 and R12 are ethyl; R5 and R17 are OH; R5, R8, Rg, R13, R14, and R15 are H; R4 is NH; R7 and R15 are Cl; and "----" in Formula | between A0 and A1, all Formula II and Formula IV "—--- are double bonds. An example of a compound of this embodiment of the invention es (NCL158): \ n H / N’ T ‘N Cl OH HO CI In r preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically able salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and Ag are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2 and R12 are cyclopentyl; R5 and R17 are OH; R6, R8, R9, R13, R14, and R16 are H; R4 is NH; R7 and R15 are Cl; and "----" in a I between A0 and A1, all Formula II and Formula IV "---—" are double bonds. An example of a compound of this embodiment of the invention includes (NCL159): \ H H / N’ T ‘N CI OH HO CI In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, ceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16 and R17 are H; R4 is NH; R7 and R15 are OCF3; and "----" in Formula I between A0 and A1, all Formula II and Formula IV "-—--" are double bonds. An example of a compound of this embodiment of the invention includes (NCL160): H H N N F of r W) F FXOF F NH.HCI O) In another preferred embodiment of the ion, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2 and R12 are methyl; R5, R6, R8, R9, R13, R14, R16 and R17 are H; R4 is NH; R7 and R15 are piperazinyl; and "----" in Formula | between A0 and A1, all Formula II and Formula IV "—--— are double bonds. An example of a compound of this embodiment of the invention includes (NCL161): H H \N/NYBLN/ In another preferred ment of the invention, the compound is a compound of Formula I, or a isomer, tautomer, pharmaceutically acceptable salt, or g thereof, wherein R1 is Formula II; R3 is O-CHz-CHg; A1 is N; A2 is NH; A0, A3, A4, A5, A6 and A7 are C; R2 is methyl; R5, R6, R8, and R9 are H; R4 is NH; R7 is CI; and "----" in Formula | between A0 and A1, and all Formula II "—--—" are double bonds. An example of a compound of this embodiment of the invention includes (NCL162): In another red embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, er, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R5, R6, R8, R9, R12, R13, R14, R16 and R17 are H; R4 is NH; R7 and R15 are SCF3; and "----" in Formula | n A0 and A1, all Formula II and Formula IV "-—--" are double bonds. An example of a compound of this embodiment of the invention includes (NCL166): H H F?: ml", TNTH H50 )F F S S F In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is a II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7,A11, A12, A13, A14 and A15, are C; R2, R6, R8, R9, R12, R13, R14, and R15 are H; R4 is NH; R7 and R15 are Cl; R5 and R17 are -NH-CH(OH)—CH3; and "----" in Formula I between A0 and A1, all Formula II and Formula IV "---- are double bonds. An e of a compound of this embodiment of the invention includes (NCL168): H H CI NH I-IN CI AOH HO)\ In another preferred embodiment of the ion, the compound is a compound of Formula I, or a stereoisomer, tautomer, ceutically acceptable salt, or prodrug thereof, wherein A0 is C; R1 is H; A2 and R4 are N; R3 is NH2; A1 is Formula VII; R2 is Formula VII and R2 is bonded to R4, forming a pyrimidine ring; "----" in Formula I between R2 and A0, and between A1 and A2 are double bonds; A22 is —N-CH-; R24, R25, R27 and R28 are H; A23, A24, A25, A26 and A27 are C; and R26 is Cl. An example of a compound of this embodiment of the invention includes (NCL179): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is NH2; A1 is N; A2 and R4 are NH; A0, A3, A4, A5, A6, and A7 are C; R5, R6, R8, and R9 are H; R2 is butyl; R7 is Cl; and "----" in a I between A0 and A1, and all Formula II "---— are double bonds. An example of a compound of this embodiment of the invention includes (NCL188): \ H NH N if 2 NH HCI In another preferred embodiment of the invention, the nd is a compound of Formula |, or a isomer, tautomer, pharmaceutically able salt, or prodrug thereof, wherein A0 is C; R1 is H; A2 and R4 are N; R3 is NH2; A1 is Formula Vll; R2 is Formula VII and R2 is bonded to R4, forming a dine ring; "----" in Formula | between R2 and A0, and between A1 and A2 are double bonds; A22 is —N—CH—; R24, R25, R27 and R28 are H; A23, A24, A25, A26 and A27 are C; and R26 is CH3. An example of a compound of this embodiment of the invention includes ] In another preferred embodiment of the invention, the compound is a compound of a I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein A0 is C; R1 is H; A2 and R4 are N; R3 is NH2; A1 is Formula Vll; R2 is Formula VII and R2 is bonded to R4, forming a pyrimidine ring; "----" in Formula | between R2 and A0, and between A1 and A2 are double bonds; A22 is —N-CH-; R24, R25, R27 and R28 are H; A23, A24, A25, A26 and A27 are C; and R26 is OH. An example of a compound of this embodiment of the invention includes (NCL196): i/‘z: / z / \ z ‘<\z :I:O N/\©\OH In another preferred embodiment of the ion, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein A0 is C; R1 is H; A2 and R4 are N; R3 is NH2; A1 is Formula Vll; R2 is Formula VII and R2 is bonded to R4, forming a pyrimidine ring; "-—--" in Formula | between R2 and A0, and between A1 and A2 are double bonds; A22 is —N-CH-; R24, R25, R27 and R23 are H; A23, A24, A25, A26 and A27 are C; and R26 is Br. An example of a compound of this embodiment of the invention includes (NCL193): In another preferred ment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein A0 is C; R1 is H; A2 and R4 are N; R3 is NH2; A1 is Formula Vll; R2 is Formula VII and R2 is bonded to R4, forming a dine ring; "-—--" in Formula | between R2 and A0, and between A1 and A2 are double bonds; A22 is —N-CH-; R24, R25, R26, R27 and R28 are H; and A23, A24, A25, A26 and A27 are C. An example of a compound of this embodiment of the ion includes (NCL199): In r preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, ceutically acceptable salt, or prodrug f, wherein A0 is C; R1 is H; A2 and R4 are N; R3 is NH2; A1 is Formula Vll; R2 is Formula VII and R2 is bonded to R4, g a pyrimidine ring; "-—--" in Formula | between R2 and A0, and between A1 and A2 are double bonds; A22 is —N-C(CH3)-; R24, R25, R27 and R28 are H; A23, A24, A25, A26 and A27 are C; and R26 is Cl. An example of a compound of this embodiment of the invention includes (NCL204): Cl \f Cl In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or g thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2, R5, R8, R9, R12, R13, R14, and R16 are H; R4 is NH; R7 and R15 are Cl; R5 and R17 are F; and "-—-—" in Formula | between A0 and A1, all Formula II and Formula IV "----" are double bonds. An example of a compound of this embodiment of the ion includes (NCL216): H H mN’ 7r \N/D/NH'HC' Cl F F CI In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically able salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2 and R12 are methyl; R5, R6, R3, R9, R13, R14, R16 and R17 are H; R4 is NH; R7 and R15 are CH3; and "-—-—" in Formula | n A0 and A1, all Formula II and Formula IV "--—-" are double bonds. An example of a compound of this embodiment of the invention includes (NCL217): In another preferred embodiment of the invention, the compound is a compound of Formula I, or a stereoisomer, tautomer, ceutically acceptable salt, or prodrug thereof, wherein R1 is Formula II; R3 is Formula IV; A1 and A10 are N; A2 and A9 are NH; A0, A3, A4, A5, A6, A7, A11, A12, A13, A14 and A15, are C; R2 and R12 are methyl; R5, R5, R8, R9, R13, R14, R16 and R17 are H; R4 is NH; R7 and R15 are t—butyl; and "--—- in Formula | between A0 and A1, all Formula II and Formula IV "---- are double bonds. An e of a compound of this embodiment of the invention includes (NCL219): H H ,N N\ N W N ] In another preferred embodiment of the invention, the compound is a compound of a I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, n A0 is C; R1 is H; A2 and R4 are N; R3 is NH2; A1 is a Vll; R2 is Formula VII and R2 is bonded to R4, forming a pyrimidine ring; "-—--" in Formula | between R2 and A0, and between A1 and A2 are double bonds; A22 is —N-CH-; R24, R25, R27 and R23 are H; A23, A24, A25, A26 and A27 are C; and R26 is CF3. An example of a compound of this embodiment of the invention es (NCL221): H H F3C NY" CF3 In r aspect of the ion, the ion is a compound selected from the list of nds presented in Figure 1. In one preferred ment, the compound is a compound seclected from the ing compounds: NCL231 to NCL275. In a further aspect, the invention is a composition comprising a compound of the invention. In yet a further aspect, the invention is a pharmaceutical composition comprising a compound of the invention together with an pharmaceutically acceptable excipient and/or carrier. In yet a further aspect, the invention is a veterinary composition comprising a compound of the invention together with an acceptable excipient and/or carrier.
Terms used herein will have their customary meanings in the art unless specified. As used herein, the term robenidine, NCL812 (also known as 1,3-bis[(E)—(4- chlorophenyl)methyleneamino]guanidine) refers to a compound having the following chemical structure: /©/\N/ Y \N/\©\\ H H / Cl CI Preferably, the protozoan agent is selected from the group of genera, sub-genera and species listed in Table 1.
Table 1 Acanthamoeba (Scienti?c classi?cation: Eukaryota; Amoebozoa; Discosea; Longamoebia; Centramoebida; Acanthamoebidae) including Acanthamoeba yxis, Acanthamoeba castellanii, Acanthamoeba comandoni, Acanthamoeba culbertsoni, Acanthamoeba divionensis, Acanthamoeba echinulata, Acanthamoeba grif?ni, Acanthamoeba hatchetti, Acanthamoeba healyi, Acanthamoeba jacobsi, Acanthamoeba Ienticulata, Acanthamoeba ensis, Acanthamoeba aniensis, Acanthamoeba palestinensis, amoeba paradivionensis, Acanthamoeba pearcei, Acanthamoeba polyphaga, Acanthamoeba pustulosa, Acanthamoeba quina, Acanthamoeba rhysodes, Acanthamoeba royreba, Acanthamoeba stevensoni, Acanthamoeba terricola, amoeba triangularis, Acanthamoeba tubiashi, Acanthamoeba sp., and unclassified Acanthamoeba.
Babesia (Scienti?c classi?cation: Eukaryota; Alveolata; Apicomplexa; Aconoidasida; Piroplasmida; Babesiidae) including Babesia bennetti, Babesia is‘ Babesia bigemina, Babesia cf. bigemina, Babesia bovis, Babesia cf. bovis, Babesia caballi, a canis (and subspecies Babesia canis canis, Babesia canis rossi and a canis vogeli), Babesia capreoli, Babesia conradae, Babesia crassa, Babesia cf. crassa GU184, Babesia divergens, a cf. divergens, Babesia cf. divergens AdL5, Babesia duncani, Babesia equi, Babesia felis, Babesia cf. felis, Babesia gibsoni, Babesia hongkongensis, a sis, Babesia lengau, a leo, a major, Babesia microti, Babesia cf. microti, Babesia cf. microti 12, Babesia motasi, Babesia muratovi, Babesia occultans, Babesia odocoilei, Babesia cf. lei, Babesia orientalis, Babesia cf. orientalis, Babesia ovata, Babesia ovis, Babesia poelea, Babesia rodhaini, Babesia vesperuginis, Babesia vitalii, Babesia sp. 'venatorum', and unclassi?ed Balamuthia (Scientific classi?cation: Eukaryota; Amoebozoa; Discosea; Longamoebia; moebida; Balamuthiidae) including Balamuthia mandrillaris Balantidium (Scientific classi?cation: Eukaryota; Alveolata; Ciliophora; acronucleata; Litostomatea; stomatia; Vestibuliferida; Balantidiidae) including Balantidium cf. coli, Balantidium ctenopharyngodoni and Balantidium entozoon.
Besnoitia (Scienti?c classi?cation: Eukaryota; Alveolata; Apicomplexa; Conoidasida; Coccidia; idiorida; Eimeriorina; Sarcocystidae) ing, Besnoitia akodoni, Besnoitia bennetti, Besnoitia ti, Besnoitia caprae, Besnoitia darlingi, Besnoitia jellisoni, Besnoitia neotomofelis, Besnoitia felisi, and tia tarandi.
Blastocystis (Scientific classification: Eukaryota; Stramenopiles) including Blastocystis cycluri, Blastocystis geocheloni, Blastocystis hominis, Blastocystis lapemi, cystis pythoni, Blastocystis ratti, and Blastocystis sp.
Chilomastix (Scienti?c classification: Eukaryota; Fornicata; Retortamonadidae) including Chilomastix caulleryi, Chilomastix mesnili andChilomastix wenrichi.
Cochlosoma (Scienti?c classi?cation: Eukaryota; Parabasalia; Trichomonadida; Trichomonadidae) including Cochlosoma anatis.
Cryptosporidium (Scienti?c classi?cation: Eukaryota; Alveolata; Apicomplexa; asida; ia; Eucoccidiorida; Eimeriorina; Cryptosporidiidae) including Cryptosporidium andersoni, Cryptosporidium i, Cryptosporidium bovis, Cryptosporidium canis, Cryptosporidium cf. bovis G2, Cryptosporidium cf. bovis GB, Cryptosporidium cf. bovis G4, Cryptosporidium cf. bovis GY, Cryptosporidium cf. molnari, Cryptosporidium cf. parvum, sporidium cf. suis, Cryptosporidium cuniculus, Cryptosporidium erinacei, Cryptosporidium fayeri, Cryptosporidium felis, Cryptosporidium fragile, Cryptosporidium galli, Cryptosporidium hominis, Cryptosporidium macropodum, Cryptosporidium meleagridis, Cryptosporidium molnari, Cryptosporidium muris, Cryptosporidium parvum, Cryptosporidium parvum mouse genotype, Cryptosporidium ryanae, Cryptosporidium saurophilum, Cryptosporidium scrofarum, Cryptosporidium serpentis, Cryptosporidium struthionis, Cryptosporidium suis, Cryptosporidium tyzzeri, Cryptosporidium ubiquitum, Cryptosporidium viatorum, Cryptosporidium wrairi, Cryptosporidium xiaoi, and unclassi?ed Cryptosporidium.
Cyclospora ti?c classi?cation: Eukaryota; Alveolata; Apicomplexa; Conoidasida; Coccidia; Eucoccidiorida; Eimeriorina; Eimeriidae) including Cyclospora cayetanensis, Cyclospora cercopitheci, pora , Cyclospora is, and Cyclospora sp.
Cystoisospora (Scienti?c classi?cation: Eukaryota; Alveolata; Apicomplexa; Conoidasida; ia; Eucoccidiorida; Eimeriorina; ystidae) including Cystoisospora belli, sospora felis, Cystoisospora ohioensis, Cystoisospora cf. ohioensis, Cystoisospora rivolta, sospora suis, and Cystoisospora .
Cytauxzoon (Scienti?c classi?cation: Eukaryota; ata; Apicomplexa; Aconoidasida; Piroplasmida; Theileriidae) including Cytauxzoon felis, Cytauxzoon manul and unclassified Cytauxzoon.
Dientamoeba (Scienti?c classi?cation: Eukaryota; Parabasalia; Tritrichomonadida; Dientamoebidae) including Dientamoeba fragilis.
Eimeria ( Scientific classification: Eukaryota; Alveolata; plexa; Conoidasida; Coccidia; Eucoccidiorida; Eimeriorina; Eimeriidae) including Eimeria acervulina, Eimeria adenoeides, Eimeria ahsata, Eimeria alabamensis, Eimeria albigulae, Eimeria alorani, a anguillae, Eimeria anseris, Eimeria antrozoi, Eimeria apionodes, Eimeria arizonensis, Eimeria arloingi, Eimeria arnyi, a auburnensis, Eimeria auritusi, Eimeria banffensis, Eimeria bovis, Eimeria brunetti, Eimeria onensis, Eimeria burdai, Eimeria cahirinensis, Eimeria callospermophili, Eimeria canadensis, Eimeria catronensis, Eimeria caviae, Eimeria chaetodipi, Eimeria chinchillae, Eimeria ari, Eimeria coecicola, Eimeria crandallis, Eimeria cylindrica, Eimeria cylindrospora, Eimeria daviesae, Eimeria dipodomysis, Eimeria dispersa, a ellipsoidalis, Eimeria exigua, Eimeria falciformis, Eimeria faurei, a flavescens, Eimeria furonis, Eimeria gallopavonis, Eimeria gruis, Eimeria hermani, Eimeria hessei, Eimeria intestinalis, Eimeria irresidua, Eimeria kri'osmanni, Eimeria lamae, Eimeria lancasterensis, Eimeria lanebarteli, Eimeria leucisci, Eimeria i, Eimeria macropodis, Eimeria niensis, Eimeria magna, Eimeria maxima, Eimeria media, Eimeria meleagrimitis, Eimeria mitis, a mivati, Eimeria cf. mivati, Eimeria myoxi, Eimeria nafuko, Eimeria necatrix, Eimeria nemethi, Eimeria nieschulzi, Eimeria oensis, Eimeria onychomysis, Eimeria ovinoidalis, Eimeria papillata, Eimeria na, Eimeria percae, Eimeria perforans, Eimeria peromysci, Eimeria phalacrocoraxae, Eimeria pilarensis, Eimeria piriformis, Eimeria polita, Eimeria porci, Eimeria praecox, a pragensis, Eimeria quokka, Eimeria ranae, Eimeria reedi, Eimeria reichenowi, Eimeria rioarribaensis, Eimeria rutili, Eimeria scabra, Eimeria scholtysecki, Eimeria separata, Eimeria setonicis, Eimeria sevilletensis, Eimeria siliculiformis, Eimeria sinensis, Eimeria stiedai, Eimeria thelialis, Eimeria subspherica, Eimeria telekii, Eimeria tenella, Eimeria cf. tenggilingi s, Eimeria suri, Eimeria tropidura, Eimeria variabilis, Eimeria vejdovskyi, a vermiformis, Eimeria vilasi, Eimeria dgensis, Eimeria wyomingensis, Eimeria zuernii, and unclassi?ed Eimeria.
Endolimax (Scientific classi?cation: ota; Amoebozoa; Archamoebae; Entamoebidae) including Endolimax nana and Endolimax piscium.
Entamoeba (Scienti?c classi?cation: Eukaryota; Amoebozoa; Archamoebae; Entamoebidae) ing Entamoeba bangladeshi, Entamoeba bovis, Entamoeba chattoni, Entamoeba coli, Entamoeba dispar, Entamoeba ecuadoriensis, Entamoeba equi, Entamoeba alis, Entamoeba hartmanni, Entamoeba histolytica, Entamoeba insolita, Entamoeba invadens, Entamoeba moshkovskii, Entamoeba muris, Entamoeba nuttalli, Entamoeba polecki, Entamoeba ranarum, Entamoeba struthionis, Entamoeba suis, and Entamoeba terrapinae.
Giardia (Scienti?c classi?cation: ota; Fornicata; Diplomonadida; Hexamitidae; Giardiinae) including Giardia ardeae, Giardia inalis (synonyms Giardia duodenalis and Giardia lamblia) (and various assemblages), Giardia i, Giardia muris, a psittaci and unclassi?ed Giardia.
Haemoproteus (Scientific classi?cation: Eukaryota; Alveolata; Apicomplexa; Aconoidasida; Haemosporida) including Haemoproteus ali, Haemoproteus belopolskyi, Haemoproteus chelodinae, Haemoproteus coatneyi, Haemoproteus columbae, Haemoproteus danilewskyii, Haemoproteus elani, Haemoproteus ator, Haemoproteus fringillae, Haemoproteus hirundinis, Haemoproteus lopolskyi, Haemoproteus iwa, Haemoproteus jenniae, Haemoproteus kopki, Haemoproteus lanii, Haemoproteus magnus, Haemoproteus majoris, Haemoproteus i, Haemoproteus micronuclearis, Haemoproteus minutus, Haemoproteus llae, Haemoproteus multipigmentatus, Haemoproteus nucleofascialis, Haemoproteus pallidulus, Haemoproteus us, Haemoproteus parabelopolskyi, Haemoproteus paranucleophilus, roteus passeris, Haemoproteus pastoris, Haemoproteus payevskyi, Haemoproteus picae, roteus ptyodactylii, Haemoproteus sacharovi, Haemoproteus sanguinis, Haemoproteus sylvae, Haemoproteus syrnii, Haemoproteus tartakovskyi, Haemoproteus turtur, Haemoproteus vacuolatus, and unclassi?ed Haemoproteus.
Hammondia (Scienti?c classi?cation: Eukaryota; Alveolata; Apicomplexa; Conoidasida; Coccidia; Eucoccidiorida; Eimeriorina; Sarcocystidae) including Hammondia hammondi, Hammondia heydorni, Hammondia trif?ttae and Hammondia sp. 00.
Hartmannella (Scientific ?cation: Eukaryota; Amoebozoa; nea; Euamoebida; Tubulinida; Hartmannellidae) including Hartmannella abertawensis, Hartmannella cantabrigiensis, Hartmannella cf. vermiformis [now known at Vermamoeba ormis ], and Hartmanella sp. zoon (Scienti?c classi?cation: Eukaryota; Alveolata; Apicomplexa; Conoidasida; Coccidia; Eucoccidiorida; Adeleorina; zoidae) including Hepatozoon americanum, Hepatozoon ayorgbor, Hepatozoon canis, Hepatozoon catesbianae, Hepatozoon cf. catesbianae, Hepatozoon clamatae, Hepatozoon cf. clamatae, Hepatozoon erhardovae, Hepatozoon felis, zoon seychellensis, Hepatozoon sipedon, Hepatozoon tuatarae, Hepatozoon ursi, and unclassified Hepatozoon.
Hexamita (Scientific classi?cation: Eukaryota; Fornicata; Diplomonadida; tidae; tinae) including Hexamita inflata, Hexamita nelsoni and Hexamita sp.
Histomonas (Scientific classification: Eukaryota; Parabasalia; chomonadida; Dientamoebidae) including Histomonas meleagridis and Histomonas sp. lsospora (Scienti?c classi?cation: Eukaryota; Alveolata; Apicomplexa; Conoidasida; Coccidia; Eucoccidiorida; Eimeriorina; Eimeriidae) including lsospora anthochaerae, lsospora gryphoni, ra hypoleucae, lsospora insularius, lsospora lesouefi, lsospora orlovi, lsospora peromysis, and lsospora robini.
Leishmania (Scienti?c classi?cation: Eukaryota; Euglenozoa; Kinetoplastida; Trypanosomatidae; Leishmaniinae) including subgenus Leishmania ding Leishmania aethiopica species complex, Leishmania aristidesi, Leishmania deanei, Leishmania donovani species complex, Leishmania hertigi, ania major species complex, Leishmania major x donovani, Leishmania mexicana species complex, Leishmania a species complex, lizard Leishmania (Leishmania adleri, Leishmania gymnodactyli, Leishmania hoogstraali, Leishmania olae, Leishmania sp. NCZQ/Iran/2007), subgenus Viannia (including Leishmania braziliensis s complex, Leishmania garnhami, Leishmania nsis species complex, Leishmania ni species complex, Leishmania lindenbergi, Leishmania naif? species complex, Leishmania utin-ensis, and unclassified Leishmania . ytozoon (Scienti?c classification: Eukaryota; Alveolata; Apicomplexa; Aconoidasida; Haemosporida) including Leucocytozoon buteonis, Leucocytozoon ryi, Leucocytozoon dubreuili, Leucocytozoon fringillinarum, ytozoon gentili, ytozoon lovati, Leucocytozoon macleani, Leucocytozoon majoris, Leucocytozoon quynzae, Leucocytozoon sabrazesi, Leucocytozoon schoutedeni, Leucocytozoon simondi, ytozoon squamatus, ytozoon toddi, Leucocytozoon ziemanni, Leucocytozoon sp., and unclassi?ed Leucocytozoon.
Naegleria (Scienti?c classification: Eukaryota; Heterolobosea; pyrenida; Vahlkamp?idae) including Naegleria americana, Naegleria oni, Naegleria angularis, Naegleria antarctica, Naegleria arctica, Naegleria australiensis, Naegleria cf. australiensis, Naegleria canariensis, Naegleria carteri, Naegleria chilensis, Naegleria clarki, Naegleria dobsoni, Naegleria dunnebackei, Naegleria endoi, Naegleria fowleri, Naegleria fultoni, Naegleria galeacystis, Naegleria gallica, Naegleria gruberi, Naegleria cf. gruberi, Naegleria indonesiensis, Naegleria italica, Naegleria jadini, Naegleria jamiesoni, Naegleria laresi, Naegleria lovaniensis, ria mexicana, Naegleria minor, Naegleria ensis, Naegleria neoantarctica, Naegleria neochilensis, Naegleria neodobsoni, Naegleria neopolaris, Naegleria pagei, Naegleria paradobsoni, Naegleria peruana, Naegleria philippinensis, Naegleria polaris, ria pringsheimi, Naegleria di, Naegleria robinsoni, Naegleria schusteri, Naegleria spitzbergeniensis, ria tenerifensis, Naegleria tihangensis, ria sp., and unclassified Naegleria.
Neospora (Scientific classi?cation: Eukaryota; Alveolata; Apicomplexa; Conoidasida; Coccidia; Eucoccidiorida; Eimeriorina; ystidae) including Neospora caninum, Neospora hughesi and Neospora sp.
Pentatrichomonas (Scientific classi?cation: Eukaryota; Parabasalia; monadida; Trichomonadidae) including Pentatrichomonas hominis.
Plasmodium (Scienti?c classification: ota; Alveolata; Apicomplexa; Aconoidasida; Haemosporida) including dium ovale, Plasmodium ale, Plasmodium simium, Plasmodium vivax, and subgenera Plasmodium (Bennettinia) (birds); Plasmodium (Giovannolaia) (birds); Plasmodium (Haemamoeba) (birds); Plasmodium (Huffia) (birds); Plasmodium (Laverania) (higher primates, includes Plasmodium falciparum); Plasmodium (Novyella) (birds); Plasmodium (Paraplasmodium) ds); Plasmodium (Plasmodium) (higher primates, includes Plasmodium brasilianum, Plasmodium cynomolgi, Plasmodium inui, Plasmodium knowlesi, dium malariae]; Plasmodium (Sauramoeba) (lizards); and Plasmodium (Vinckeia).
Sappinia (Scientific classification: Eukaryota; Amoebozoa; Discosea; Longamoebia; Thecamoebida) including Sappinia diploidea, Sappinia pedata and Sappinia sp. ystis (Scientific classi?cation: Eukaryota; Alveolata; Apicomplexa; Conoidasida; Coccidia; Eucoccidiorida; Eimeriorina; ystidae) including Sarcocystis albifronsi, Sarcocystis alces, Sarcocystis alceslatrans, Sarcocystis anasi, Sarcocystis arctica, Sarcocystis arieticanis, Sarcocystis atheridis, Sarcocystis aucheniae, Sarcocystis buffalonis, Sarcocystis calchasi, Sarcocystis campestris, Sarcocystis canis, Sarcocystis capracanis, ystis capreolicanis, Sarcocystis cf. clethrionomyelaphis JJH-2013, Sarcocystis columbae, Sarcocystis i, Sarcocystis cruzi, Sarcocystis cf. cruzi, Sarcocystis dasypi, Sarcocystis dispersa, Sarcocystis elongata, Sarcocystis falcatula, Sarcocystis cf. falcatula, Sarcocystis fayeri, ystis felis, Sarcocystis cf. felis WACF-2013, ystis fusiformis, ystis gallotiae, Sarcocystis gigantea, Sarcocystis gracilis, Sarcocystis grueneri, Sarcocystis hardangeri, Sarcocystis a, Sarcocystis hjorti, Sarcocystis hominis, Sarcocystis lacertae, Sarcocystis lamacanis, Sarcocystis yi, Sarcocystis eriana, Sarcocystis moulei, Sarcocystis , Sarcocystis muris, Sarcocystis nesbitti, Sarcocystis neurona [agent of equine protozoal myeloencephalitis (EPM)], Sarcocystis cf. neurona, Sarcocystis neurona-like protozoan, Sarcocystis ovalis, Sarcocystis oviformis, Sarcocystis ramphastosi, Sarcocystis rangi, Sarcocystis rangiferi, Sarcocystis rileyi, ystis rodentifelis, Sarcocystis scandinavica, Sarcocystis silva, Sarcocystis sinensis, Sarcocystis singaporensis, ystis suihominis, Sarcocystis ta, Sarcocystis tarandi, Sarcocystis tarandivulpes, Sarcocystis tenella, ystis truncata, Sarcocystis turdusi, Sarcocystis wobeseri, Sarcocystis , Sarcocystis zuoi, and unclassi?ed ystis.
Tetratrichomonas tific classification: Eukaryota; Parabasalia; Trichomonadida; Trichomonadidae) including Tetratrichomonas i, Tetratrichomonas buttreyi, Tetratrichomonas gallinarum, Tetratrichomonas Iimacis, Tetratrichomonas prowazeki, Tetratrichomonas undula, and unclassi?ed Tetratrichomonas.
Theileria ti?c classification: Eukaryota; ata; Apicomplexa; Aconoidasida; Piroplasmida; Theileriidae) including Theileria annae, Theileria ta, Theileria annulata strain Ankara Theileria bicornis, Theileria brachyuri, Theileria i, Theileria cf. buffeli A MEG-2013, Theileria cf. buffeli B, Theileria cf. buffeli C, Theileria cf. buffeli MC— 2012, Theileria capreoli, Theileria cervi, Theileria equi, Theileria fuliginosus, Theileria lestoquardi, Theileria cf. lestoquardi (Atbara), Theileria cf. lestoquardi G4, ria cf. lestoquardi G6, Theileria Iuwenshuni, Theileria mutans, Theileria cf. mutans 3, Theileria cf. mutans A 13, Theileria cf. mutans B MEG-2013, Theileria cf. mutans C MEG-2013, Theileria orientalis, Theileria orientalis complex isolate 9172, Theileria orientalis complex isolate 9196, ria alis strain Shintoku Theileria ovis, Theileria cf. ovis G4, ria cf. ovis GB, Theileria , parva, Theileria parva bovis, Theileria parva Iawrencei, Theileria parva parva, Theileria parva strain Muguga Theileria penicillata, Theileria separata, Theileria sergenti, Theileria sinensis, Theileria cf. sinensis, Theileria cf. sinensis MC- 2012, Theileria taurotragi, Theileria uilenbergi, ria velifera, Theileria cf. velifera A, Theileria cf. velifera A MEC- 2013, Theileria cf. velifera B, Theileria cf. velifera B MEG-2013, Theileria cf. velifera S ncerus caffer, Theileria youngi, Theileria sp., and unclassi?ed ria.
Toxoplasma (Scienti?c fication: Eukaryota; Alveolata; plexa; Conoidasida; Coccidia; Eucoccidiorida; Eimeriorina; Sarcocystidae) ing Toxoplasma gondii.
Trichomonas (Scienti?c classi?cation: Eukaryota; salia; Trichomonadida; Trichomonadidae) including Trichomonas canistomae, Trichomonas equibuccalis, monas gallinae, Trichomonas stableri, Trichomonas tenax, and Trichomonas vaginalis.
Tritrichomonas (Scienti?c classification: Eukaryota; Parabasalia; Tritrichomonadida; Tritrichomonadidae) including Tritrichomonas augusta, Tritrichomonas foetus, Tritrichomonas mobilensis, Tritrichomonas muris, Tritrichomonas nonconforma, and Tritrichomonas suis.
Trypanosoma (Scienti?c classification: Eukaryota; Euglenozoa; Kinetoplastida; Trypanosomatidae) including SubgenusDuttonella (Trypanosoma vivax and Trypanosoma sp. T78), SubgenusHerpetosoma (Trypanosoma blanchardi, Trypanosoma lewisi, Trypanosoma rabinowitschae, Trypanosoma rangeli, Trypanosoma sp. SJP-2011), SubgenusNannomonas (Trypanosoma congolense, Trypanosoma simiae, Trypanosoma simiae Tsavo, Trypanosoma sp. Fly9), SubgenusSchizotrypanum (Trypanosoma cruzi, Trypanosoma dionisii, Trypanosoma erneyi, Trypanosoma vespertilionis), Trypanosoma with unspecified us (Trypanosoma avium, Trypanosoma cf. avium TRM-2012, Trypanosoma bennetti, osoma binneyi, Trypanosoma boissoni, Trypanosoma caninum, Trypanosoma carassii, Trypanosoma cascavelli, Trypanosoma cervi, Trypanosoma chattoni, Trypanosoma chelodinae, osoma s, Trypanosoma ini, Trypanosoma copemani, Trypanosoma corvi, Trypanosoma vium, Trypanosoma cyclops, osoma danilewskyi, Trypanosoma desterrensis, Trypanosoma everetti, Trypanosoma evotomys, Trypanosoma i, Trypanosoma gallinarum, Trypanosoma godfreyi, Trypanosoma granulosum, Trypanosoma grayi, Trypanosoma grosi, Trypanosoma hastatus, Trypanosoma irwini, Trypanosoma kuseli, Trypanosoma leeuwenhoeki, Trypanosoma livingstonei, Trypanosoma mega, Trypanosoma melophagium, Trypanosoma microti, Trypanosoma minasense, Trypanosoma murmanensis, Trypanosoma i, Trypanosoma nabiasi, Trypanosoma neveulemairei, Trypanosoma nudigobii, Trypanosoma ophiocephali, Trypanosoma otospermophili, Trypanosoma percae, Trypanosoma pestanai, Trypanosoma pleuronectidium, Trypanosoma ralphi, Trypanosoma ranarum, Trypanosoma rotatorium, Trypanosoma scelopori, Trypanosoma siniperca, Trypanosoma terrestris, Trypanosoma ri, Trypanosoma therezieni, Trypanosoma triglae, Trypanosoma varani), usTrypanozoon (Trypanosoma , Trypanosoma cf. brucei Msubugwe, Trypanosoma equiperdum, Trypanosoma evansi, and unclassi?ed Trypanosoma).
Tyzzeria ti?c classification: ota; Alveolata; Apicomplexa; Conoidasida; Coccidia; idiorida; Eimeriorina; Eimeriidae) species.
Wenyonella (Scientific classification: Eukaryota; Alveolata; Apicomplexa; Conoidasida; Coccidia; Eucoccidiorida; Eimeriorina; Eimeriidae) species.
BRIEF DESCRIPTION OF THE GS Further features of the present invention are more fully described in the following description of several non-limiting embodiments thereof. This description is included solely for the es of ifying the present invention. It should not be understood as a restriction on the broad summary, disclosure or description of the invention as set out above. The description will be made with reference to the accompanying drawings in which: Figure 1 presents the chemical name and chemical structure of the compounds NCL001 to NCL230; Figure 2 is a graph illustrating the activity of NCL099 against a alis; Figure 3 is a graph illustrating the effect of NCL812 and metronidazole on the adherence of Giardia duodenalis trophozoites; Figure 4 is a graph illustrating the activity of NCL812 against Giardia duodenalis; Figure 5 is a graph illustrating the activity of NCL062 against Giardia duodenalis; Figure 6 is a graph illustrating the activity of Metronidazole against Giardia alis; Figure 7 is a graph illustrating the ocyte lysis based on n-fold minimum inhbitory concentration; Figure 8 presents photographs demonstrating changes in the ultrastructure of Giardia trophozoites exposed to NCL812. A—B: control 0.1% DMSO, C: metronidzaole l, D-G: NCL812 exposed trophozoites (1hr); Figure 9 is a graph illustrating the cumulative release of NCL812 and NCL099 from Formulation B according to e 7; Figure 10 is a graph rating the activity of NCL compounds at 10 pM against T. brucei (black) and L. donovani (grey); Figure 11 is a table illustrating the physicochemical and metabolic characteristics of nine NCL compounds; Figure 12 is a graph illustrating the plasma concentration versus time profiles for NCL026, NCL195, NCL259 and NCL812; and Figure 13 is a graph illustrating the plasma concentrations of NCL195 in male Swiss outbred mice following IP administration at an e dose of 43 mg/kg.
DESCRIPTION OF EMBODIMENTS General ] Before bing the present invention in detail, it is to be understood that the invention is not limited to particular exemplified s or compositions disclosed herein. It is also to be understood that the ology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting.
] All ations referred to herein, including patents or patent applications, are incorporated by reference in their entirety. However, applications that are mentioned herein are referred to simply for the purpose of describing and disclosing the procedures, protocols, and reagents referred to in the publication which may have been used in connection with the invention. The citation of any publications referred to herein is not to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
In on, the ng out of the present invention makes use of, unless otherwise indicated, conventional microbiological techniques within the skill of the art. Such conventional techniques are known to the skilled worker.
As used herein, and in the appended claims, the singular forms "a", "an", and "the" include the plural unless the context clearly indicates otherwise.
Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. gh any materials and methods similar to, or equivalent to, those described herein may be used to carry out the present invention, the preferred materials and methods are herein described.
The invention described herein may include one or more ranges of values (e.g. size, concentration, dose etc). A range of values will be understood to include all values within the range, ing the values defining the range, and values adjacent to the range that lead to the same or substantially the same outcome as the values immediately adjacent to that value which define the boundary of the range.
The pharmaceutical or veterinary compositions of the invention may be administered in a variety of unit dosages depending on the method of administration, target site, physiological state of the t, and other medicaments administered. For example, unit dosage form suitable for oral administration include solid dosage forms such as powder, tablets, pills, and es, and liquid dosage forms, such as elixirs, , solutions and suspensions.
The active ingredients may also be administered parenterally in sterile liquid dosage forms.
Gelatin capsules may n the active ingredient and inactive ingredients such as powder carriers, glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, c acid, sodium saccharin, talcum, magnesium carbonate, and the like.
The phrase "therapeutically effective amount" as used herein refers to an amount sufficient to inhibit protozoan growth associated with a oan infection or colonisation. That is, reference to the administration of the therapeutically effective amount of a compound of Formula | according to the methods or compositions of the invention refers to a therapeutic effect in which substantial oacidal or protozoastatic activity causes a substantial inhibition of protozoan ion. The term "therapeutically effective amount" as used herein, refers to a sufficient amount of the composition to provide the desired biological, therapeutic, and/or prophylactic result. The desired s include ation of protozoan infection or colonisation or reduction and/or ation of the signs, symptoms, or causes of a disease, or any other desired alteration of a ical system. An ive amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. In relation to a pharmaceutical or veterinary composition, effective amounts can be dosages that are recommended in the modulation of a diseased state or signs or symptoms thereof. ive amounts differ depending on the composition used and the route of administration employed.
Effective s are routinely optimized taking into consideration pharmacokinetic and pharmacodynamic characteristics as well as various s of a particular patient, such as age, weight, gender, etc and the area affected by disease or disease causing microbes.
As referred to , the terms "treatment" or "treating" refers to the full or partial removal of the symptoms and signs of the condition. For example, in the treatment of a oan infection or colonisation, the treatment completely or partially s the signs of the infection. Preferably in the treatment of infection, the ent reduces or eliminates the infecting protozoan pathogen leading to microbial cure.
As referred to herein, the term "protozoa" refers to members of a large domain of eukaryotic unicellular microorganisms. Typically a few micrometres in length, protozoa have a number of shapes, g from spheres to rods and spirals and can be present as individual cells or t in linear chains or clusters of variable numbers and shape. Preferably the terms "protozoa" and its adjectives "protozoan protozoal" refer to protozoa. The terms may refer to an antiprotozoal-sensitive strain or an otozoal-resistant strain.
Referred to herein, the term "resistant oa" refers a protozoa isolate that demonstrates resistance to anyone of the following antimicrobial agents listed in Table 2.
Table 2: Antimicrobial agents Chemical Class 4-aminoquinoline Amodiaquine, chloroquine, hydroxychloroquine, piperaquine (bis- 4-amino uinoline 8-aminoquinoline ine, pamaquine, Primaquine, tafenoquine Acetamide Thiolutin Acridine d e Acri?avine, mepacrine quinacrine Alk lphosphocholine Miltefosine All lamine Terbinafine Amino-l cosides m cin Aminophenanthridium Homidium, isometamidium chloride, Aminop ridine antimalarials MMV390048 Antimonials, pentavalent Sodium stibo-luconate, me-lumine antimoniate Arsenicals lent & pentavalent) Acetarsol (5+), nol (3+), carbarsone (5+), difetarsone (5+), glycobiarsol (5+), melarsomine (3+), melarsoprol (3+), one + 3+ roxarsone 5+ ,t , oxophenarsine , parsamide 5+ Ar laminoalcohol Halofantrine, lumefantrine, quinine/quinidine Azo naphthalene d es Tr pan blue, tr pan red Azoles (triazoles and imidazoles) Albaconazole, itraconazole, ketoconazole, posoconazole, ravuconazole Benzamide Zoxamide Benzenediol atrol Benzimidazoles and probenzimidazoles Albendazole, dazole, febantel, mebendazole, omeprazole Bic clohex lammonium Fumao illin Carbamate Disulfiram Cinnamamido adenosine Purom cin Coumarin Flocoumafen Diamidines Amicarbalide, diminazene diaceturate, imidocarb dipropionate, pafuramidine, pentamidine isethionate, phenamidine isethionate, propamidine, stilbamidine Dichloroacetamide nide e Difluorometh lornithine Eflornithine s nthase inhibitors ——inhibitors benzoic acid quinolones Guanidines Chloroproguanil, cycloguanil, lauroguadine, nil, Robenidine nated 8-hydroxyquinoline lodoquinol, chlorquinaldol, tilbroquinol, broxyquinoline, diiodoh drox ouinoline, clioquinol Hydroxyoxo-cyclohexenecarbaldehyde Sethoxydim, tralkoxydim, alloxydim, clethodim and cycloxydim oxime H drox quinolones olate, decoquinate nequunate Imidazolo oiperazine Kaf156 lsoquinoline Emetine/deh droemetine Lincosamides mycin, lincomycin Macrolides omycin, clarithromycin, erythromycin, roxithromycin, Soiram cin Meth Iquinoiinium Miscellaneous Naphthoquinones Naphth ridine Nitrobenzamides urans Nifurtimox, furaltodone, furazolidone, nifuratel, nifuroxime, nifursol Nitroimidazoles Azanidazole, benznidazole, carnidazole, dimetridazole, fexnidazole, dazole, metronidazole, nimorazole, ornidazole, propenidazole, ronidazole, satranidazole, secnidazole, ternidazole, tinidazole Nitrothiazoles Nitazoxanide, aminitrozole (nithiamide), forminitrazole, niridazole, tenonitrozole metaiiic antiprotozoai Oxabcroie inciudin- benzoxaboroies Phencxyphenoi phen Isulfamide Phosphonic acid derivative Phosphonometh I-I cine Phosphoramidothioic acid Poi ene Polyetherionophores Laidlomycin, lasalocid, micin, monensin, narasin, salinom cin, semduramicin Polypeptide Bacitracin (zinc, ene disalicylate), cecropins, cyclosporins, dermaseptin, maoainins, tach plesin, thiostrepton Polysuifonated naphthyiamine Prop Iphosphonic acid Purinamine P razolopran — P razolop rimidine Pyridinois P rimidine P rrolidinediol Quinazolinone Quinoline Mefloquine nequmate meth quate qumfamide tiliqumol Quinexaiine Rifam cin Spiroindolone KAE609 formerl NITD609 , ciparoamin Strobilurin Fluac o rim, azox strobin, tri?ox n, dimox strobin Sulfonamides Sulfadiazine, sulfadimethoxine, sulfadoxine, sulfaguanidine, sulfamethazine (sulfadimidine), sulfamethoxazole, sulfanitran, sulfaquinoxaline, sulfamethoxypyrazine, cyazofamid Sulphone e Tetracyclines Chlortetracycline, doxycycline, oxytetracycline, tetracycline, tiec cline Thiophenone Thiolactom cin Translation elongation factor 2 (eEF2) DDD107498 inhibitor Triazine Clazuril, diclazuril, ponazuril, toltrazuril Triazole Bitertanol Trioxane (sesquiterpene lactones, Artemether, artesunate, dihydroartemisinin, artemotil, artemisinin, sinins arteether, artemisone Trioxolane including ozonides) Arterolane, 02277, 02439 Pharmaceutically and veterinary acceptable salts e salts which retain the biological effectiveness and properties of the nds of the present disclosure and which are not biologically or otherwise undesirable. In many cases, the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. able base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases e, but are not limited to, salts of primary, secondary and ry amines, such as by way of example only, alkyl amines, dialkyl , trialkyl amines, substituted alkyl amines, di(subsrituted alkyl) amines, tri(substituted alkyl) amines, alkenyl , dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted l) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl , trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) , tri(cycloalkenyl) amines, substituted cycloalkenyl , disubstituted cycloalkenyl amines, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, eroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, tuted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, cyclic, and the like. Also ed are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or aryl group.
Pharmaceutically and veterinary acceptable acid addition salts may be ed from inorganic and organic acids. The inorganic acids that can be used include, by way of e only, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. The organic acids that can be used include, by way of example only, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
The pharmaceutically or nary able salts of the compounds useful in the present disclosure can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. lly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
Lists of suitable salts are found in Remington's Pharmaceutical Sciences. 17th ed., Mack Publishing Company, Easton, Pa. (1985), p. 1418, the sure of which is hereby incorporated by reference. Examples of such acceptable salts are the iodide, acetate, phenyl acetate, trifluoroacetate, acryl ate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, benzoate, o-acetoxybenzoate, naphthalene benzoate, bromide, isobutyrate, phenylbutyrate, v-hydroxybutyrate, oxybutyrate, - |,4-dioate, hexyne-l,4-dioate, - 1,6—dioate, caproate, caprylate, chloride, cinnamate, citrate, decanoate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, te, mandelate, mesylate, nicotinate, otinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, propanesulfonate, ethanesulfonate, 2- hydroxyethanesulfonate, merhanesulfonate, naphthalene—l-sulfonate, naphthalenesulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like.
The pharmaceutical or veterinary compositions of the invention may be formulated in conventional manner, together with other pharmaceutically acceptable ents if desired, into forms suitable for oral, parenteral, or topical administration. The modes of administration may include parenteral, for example, intramuscular, subcutaneous and enous stration, oral administration, topical administration and direct administration to sites of infection such as intraocular, intraaural, terine, intranasal, intramammary, intraperitoneal, intralesional, etc.
The pharmaceutical or veterinary itions of the invention may be formulated for oral administration. Traditional inactive ingredients may be added to provide desirable , taste, stability, buffering capacity, dispersion, or other known desirable features. es include red iron oxide, silica gel, sodium laurel sulphate, titanium dioxide, edible white ink, and the like. tional diluents may be used to make compressed tablets.
Both tablets and capsules may be manufactured as sustained-release compositions for the continual release of medication over a period of time. Compressed tablets may be in the form of sugar coated or film coated tablets, or enteric-coated tablets for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain colouring and/or flavouring to se patient compliance. As an example, the oral formulation comprising compounds of the invention may be a tablet sing any one, or a combination of, the following excipients: calcium hydrogen ate dehydrate, microcrystalline cellulose, e, hydroxypropyl methyl cellulose, and talc.
The compositions described herein may be in the form of a liquid formulation.
Examples of preferred liquid compositions include solutions, emulsions, injection solutions, solutions contained in capsules. The liquid formulation may comprise a solution that includes a therapeutic agent dissolved in a solvent. Generally, any solvent that has the desired effect may be used in which the therapeutic agent ves and which can be administered to a subject.
Generally, any concentration of therapeutic agent that has the desired effect can be used. The formulation in some variations is a solution which is rated, a saturated or a supersaturated solution. The solvent may be a pure t or may be a mixture of liquid solvent components. In some variations the solution formed is an in situ g ation. Solvents and types of solutions that may be used are well known to those versed in such drug delivery logies.
The composition bed herein may be in the form of a liquid suspension. The liquid suspensions may be ed according to standard procedures known in the art. es of liquid suspensions include micro-emulsions, the formation of complexing compounds, and stabilising suspensions. The liquid suspension may be in undiluted or concentrated form. Liquid suspensions for oral use may contain suitable preservatives, antioxidants, and other excipients known in the art functioning as one or more of dispersion agents, suspending , thickening agents, emulsifying agents, wetting agents, solubilising agents, stabilising , flavouring and sweetening agents, ing agents, and the like. The liquid suspension may contain glycerol and water.
The composition described herein may be in the form of an oral paste. The oral paste may be prepared according to standard procedures known in the art.
The composition is described herein may be in the form of a liquid formulation for injection, such as intra-muscular injection, and prepared using methods known in the art. For example, the liquid formulation may contain polyvinylpyrrolidone K30 and water.
The composition is described herein may be in the form of topical preparations.
The topical preparation may be in the form of a lotion or a cream, prepared using methods known in the art. For example, a lotion may be formulated with an aqueous or oily base and may e one or more excipients known in the art, functioning as viscosity enhancers, emulsifying agents, fragrances or perfumes, preservative agents, chelating agents, pH modifiers, antioxidants, and the like. For example, the topical formulation comprising one or more compounds of the invention may be a gel comprising anyone, or a combination of, the following excipients: PEG 8000, PEG 4000, PEG 200, ol, propylene glycol. The NCL812 compound may further be formulated into a solid dispersion using SoluPlus (BASF, www.soluplus.com) and ated with anyone, or a combination of, the following excipients: PEG 8000, PEG 4000, PEG 200, glycerol, and propylene glycol.
For aerosol administration, the composition of the invention is ed in a finely divided form together with a non-toxic surfactant and a propellant. The surfactant is preferably soluble in the propellant. Such surfactants may include esters or partial esters of fatty acids.
The compositions of the invention may alternatively be formulated for delivery by injection. As an example, the nd is delivered by ion by any one of the following routes: intravenous, intramuscular, intradermal, intraperitoneal, and aneous.
The compositions of the invention may atively be ated using nanotechnology drug ry techniques such as those known in the art. Nanotechnology- based drug delivery systems have the advantage of improving bioavailability, patient ance and ng side effects.
The formulation of the composition of the invention includes the preparation of nanoparticles in the form of nanosuspensions or nanoemulsions, based on compound solubility.
Nanosuspensions are dispersions of nanosized drug particles ed by bottom—up or top— down technology and stabilised with suitable excipients. This ch may be applied to the compounds of the invention which can have poor aqueous and lipid solubility, in order to enhance saturation solubility and improve dissolution characteristics. An example of this technique is set out in Sharma and Garg (2010) (Pure drug and polymer-based nanotechnologies for the improved solubility, stability, bioavailability, and targeting of anti-HIV drugs. Advanced Drug Delivery Reviews, 62: p. 491-502). Saturation solubility will be understood to be a compound-specific constant that depends on temperature, properties of the dissolution medium, and particle size (<1—2 pm).
The composition of the ion may be provided in the form of a nanosuspension. For nanosuspensions, the increase in the surface area may lead to an se in saturation solubility. Nanosuspensions are colloidal drug ry systems, consisting of particles below 1 pm. Compositions of the invention may be in the form of nanosuspensions including nanocrystalline suspensions, solid lipid nanoparticles (SLNs), polymeric nanoparticles, nanocapsules, polymeric micelles and dendrimers. Nanosuspensions may be prepared using a top—down approach where larger particles may be reduced to nanometre dimensions by a variety of techniques known in the art including wet-milling and high-pressure homogenisation. Alternatively, nanosuspensions may be prepared using a bottom—up technique where controlled precipitation of les may be carried out from solution.
The composition of the ion may be provided in the form of a nanoemulsion.
Nanoemulsions are typically clear oil-in-water or water-in-oil biphasic systems, with a droplet size in the range of 100—500 nm, and with compounds of st t in the hydrophobic phase. The preparation of ulsions may improve the solubility of the compounds of the invention bed , leading to better bioavailability. Nanosized suspensions may include agents for electrostatic or steric stabilisation such as polymers and tants. Compositions in the form of SLNs may comprise biodegradable lipids such as triglycerides, ds, waxes and emulsifiers such as soybean in, egg lecithin, and mers. The preparation of a SLN preparation may involve dissolving/dispersing drug in melted lipid ed by hot or cold homogenisation. If hot homogenisation is used, the melted lipidic phase may be dispersed in an aqueous phase and an emulsion prepared. This may be solidified by cooling to achieve SLNs. If cold homogenisation is used, the lipidic phase may be solidified in liquid nitrogen and ground to micron size. The resulting powder may be subjected to high-pressure homogenisation in an aqueous surfactant solution.
The Compounds of Formula l as described herein may be dissolved in oils/liquid lipids and stabilised into an emulsion formulation. Nanoemulsions may be prepared using high- and low-energy droplet reduction techniques. High-energy methods may include high-pressure homogenisation, ultrasonication and microfluidisation. If the low—energy method is used, solvent diffusion and phase inversion will generate a spontaneous nanoemulsion. Lipids used in nanoemulsions may be selected from the group comprising triglycerides, soybean oil, safflower oil, and sesame oil. Other components such as emulsifiers, antioxidants, pH modifiers and preservatives may also be added.
The composition may be in the form of a controlled-release formulation and may include a degradable or gradable r, hydrogel, organogel, or other physical construct that modifies the release of the compound. It is understood that such ations may include additional inactive ingredients that are added to provide desirable colour, stability, buffering capacity, dispersion, or other known desirable features. Such formulations may further include mes, such as emulsions, foams, micelles, ble yers, liquid crystals, phospholipid dispersions, lamellar layers and the like. Liposomes for use in the invention may be formed from standard vesicle-forming lipids, generally including neutral and negatively charged phospholipids and a , such as cholesterol.
The formulations of the ion may have the advantage of increased solubility and/or stability of the compounds, particularly for those formulations prepared using nanotechnology ques. Such increased stability and/or stability of the compounds of a I may improve bioavailability and e drug exposure for oral and/or parenteral dosage forms.
Throughout this specification, unless the context requires otherwise, the word "comprise" or variations such as ises" or "comprising", will be understood to imply the inclusion of a stated r or group of integers but not the exclusion of any other integer or group of integers.
EXAMPLES EXAMPLE 1: ation of NCL812 analogues.
Materials and Methods NCL812 Analytical grade NCL812 with a defined potency of 960 mg/g (Le. 96%) was obtained. The powder was stored in a sealed sample container out of direct sunlight and at room temperature at the study site. ts (1 mL) of stock solution (containing 25.6 mg/mL of NCL812 in DMSO) were prepared and stored at -80°C and defrosted immediately before use.
Synthesising and Testing of NCL812 Analogues Analogues NCL001 to NCL275, as identified in Figure 1, were synthesised using standard methods in the art. As an example, the s used to manufacture compounds NCL097; NCL157; NCL179; NCL188; NCL195; and NCL196 are as follows: NCL 097 (2,2’-bis[(3,4,5-trihydroxyphenyl)methylene]carbonimidic dihydrazide hydrochloride) A sion of 3,4,5-trihydroxybenzaldehyde (412.0 mg, 2.673 mmol, 2.21 eq.) and N,N'-diaminoguanidine hydrochloride (152.0 mg, 1.211 mmol) in EtOH (5 mL) was subjected to microwave irradiation (150 W) at 100 °C for 10 min. The reaction was then allowed to cool to ambient temperature. The resulting precipitate was collected and washed with chilled EtOH (5 mL) and Et20 (5 mL) to afford the carbonimidicdihydrazide (369.0 mg, 77%) as a pale brown solid.M.P. 292°C (Decomp.).1H NMR (300 MHz, DMSO-d6) 6 9.06 (br s, 6H), 8.25 — 8.01 (m, 4H), 6.83 (s, 4H). 130 NMR (75 MHz, DMSO-d6) 5 152.2, 149.7, 146.2, 136.5, 123.7, 107.4.
LRMS(ESI+): 361.95 [M + 11*.
NCL157 (2,2’-bis[(2-aminochlorophenyl)methylene]carbonimidic dihydrazide hydrochloride) Synthesis of 2—aminoch/oro-N-methoxy-N-mez‘hy/benzamide. To a solution of 2-aminochlorobenzoic acid 1 g, 33.041 mmol), N,O—dimethylhydroxylamine hydrochloride (5.7504 g, 58.954 mmol, 1.78 eq.), N-(3-dimethylaminopropyl)—N’- ethylcarbodiimide hydrochloride (7.7925 g, 40.649 mmol, 1.23 eq.) and N-hydroxybenzotriazole hydrate (5.2371 g, 38.793 mmol (anhydrous basis), 1.17 eq.) in DMF (100 mL) was added diisopropylethylamine (18.0 mL, 13.4 g, 104 mmol, 3.15 eq.) and the brown solution stirred at ambient temperature for 7 h. The reaction was then concentrated in vacuo before dilution with 1M NaOH (100 mL) and extracting with CH2CI2 (3 X 100 mL) The ed organic extracts were washed with 1M HCI (100 mL) before drying over MgSO4 and concentrating in vacuo to afford a brown syrup. This oil was then further dried at 60 °C under high vacuum to afford the crude Weinreb amide (7.021 g, 99%) as a brown syrup that crystallised on standing. The crude al was used without further purification. 1H NMR (400 MHz, CDCI3) 6 7.24 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 18 Hz, 1H), 6.54 (dd, J = 8.4, 1.9 Hz, 1H), 4.75 (s, 2H), 3.48 (s, 3H), 3.24 (s, 3H).13C NMR (101 MHz, CDCI3) 6 169.2, 148.4, 137.1, 130.6, 116.6, 116.1, 115.0, 61.1, 34.0. sis of 2—aminochlorobenzaldehyde. Crude 2-amino—4-chloro-N- methoxy—N-methylbenzamide (751.1 mg, 3.532 mmol) was broken up into ca. 120 mg batches and each dissolved in THF (10 mL) and cooled to 0 "C before LiAlH4 (2M in THF, 0.5 mL) was added to each and the ons stirred for 16 h, allowing the reactions to achieve room temperature. The reactions were ed with saturated NH4C| (1 mL) before being combined, diluted with saturated NaHC03 (160 mL) and extracted with CHCI3 (2 x 150 mL, 1 x 75 mL). The ed organics were dried over MgSO4 and concentrated in vacuo to afford the crude benzaldehyde (463.3 mg, 85%) as yellow/orange crystals. The material was used without further purification. 1H (400 MHz, CD3OD) 9.77 (d, J = 0.7 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 6.83 — 6.71 (m, 1H), 6.63 (dd, J = 8.4, 1.9 Hz, 1H). 13C NMR (101 MHz, CD3OD) 6 194.6, 153.0, 142.5, 138.4, 116.8, 116.1. [001 89] Synthesis of 2, 2 ’-bis[(2-amino—4—ch/orophenyl)methy/enejcarbonimidic dihydrazide hydrochloride. A suspension of 2— amino- 4- chlorobenzaldehyde (128.0 mg, 0.823 mmol, 1.78 eq.) and N,N’-diaminoguanidine hydrochloride (58.0 mg, 0.462 mmol) in EtOH (2 mL) was subjected to microwave irradiation (100 W) at 60°C for 5 minutes. Most t was then removed in vacuo, EtOH (1 mL) was added and the flask was transferred to the freezer to effect crystallisation. The resulting precipitate was collected and washed with EtOH (1 mL) to afford the carbonimidicdihydrazide (21.0 mg, 13%) as a pale yellow solid. 1H NMR (400 MHz, DMSO—de) 6 11.71 (br s, 2H), 8.40 (s, 2H), 8.37 (s, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 2.0 Hz, 2H), 6.73 (br s, 4H), 6.59 (dd, J = 8.3, 2.0 Hz, 2H). 13c NMR (101 MHz, DMSO—ds) 5 152.1, 151.5, 148.9, 136.0,134.7, 115.1, 114.5,112.8.
NCL179 (4,6-bis(2—(4-chlorobenzylidene)hydrazinyl)pyrimidinamine) A suspension of o—4,6-dihydrazinylpyrimidine (67.3 mg, 0.434 mmol) and robenzaldehyde (198.8 mg, 1.414 mmol, 3.26 eq.) in EtOH (25 mL) was heated at reflux for 16 h. After this time, the condenser was removed and the solution trated to approximately 1 mL and the resulting precipitate filtered hot and washed with EtZO (10 mL) to afford the aminopyrimidine (42.8 mg, 25%) as an off—white amorphous powder. MP. 275 °C (Decomp.). 1H NMR (400 MHz, DMSO) 6 10.70 (s, 2H), 8.02 (s, 2H), 7.67 (d, J = 8.4 Hz, 4H), 7.52 (d, J = 8.4 Hz, 4H), 6.28 (s, 1H), 5.85 (s, 2H). 13C NMR (101 MHz, 162.8, 162.6, 138.8, 134.1, 133.1, 128.9, 127.6, 73.5.
NCL188 ((E)(1-(4-chIorophenyl)pentylidene)hydrazinecarboximidamide hydrochloride) A suspension of 1-(4-ch|oropheny|)pentanone (1.8319 g, 9.3146 mmol, 1.95 eq.) and aminoguanidine hydrochloride (527.6 mg, 4.773 mmol) in EtOH (15 mL) was heated at 65 °C for 16 h. The crude was cooled to ambient temperature before being diluted with EtZO (60 mL) and cooled to 0 °C to precipitate unreacted aminoguanidine hydrochloride (174.5 mg). The mother liquors were then concentrated in vacuo and the residue dissolved in Et20 (20 mL). The solution was then boiled and hexanes (10 mL) added to afford the caboximidamide as a cream solid. 1H NMR (400 MHz, DMSO)611.54(s, 1H), 7.99 (d, J = 8.7 Hz, 2H), 7.90 (s, 3H), 7.47 (d, J = 8.6 Hz, 2H), 2.91 — 2.82 (m, 2H), 1.48 — 1.32 (m, 4H), 0.89 — 0.84 (m, 3H). 13C NMR (101 MHz, DMSO)6156.2, 153.8, 134.8, 134.4, 128.7, 128.4, 28.1, 26.6, 22.0, 13.8 NCL195 (4,6-bis(2—((E)—4—methylbenzylidene)hydrazinyl)pyrimidin—2-amine) A suspension of o-4,6-dihydrazinopyrimidine (58.9 mg, 0.380 mmol) and 4-methylbenzaldehyde (0.10 mL, 100 mg, 0.832 mmol, 2.19 eq.) in EtOH (4 mL) was heated at reflux for 16 h. The reaction mixture was cooled to t temperature before collecting the —like precipitate, washing with EtZO (20 mL). The 'pellets' were then crushed and the solid further washed with EtZO (10 mL) to afford the pyrimidine (85.8 mg, 63%) as a white 'fluffy' powder. M.P. 274-276 °C. 1H NMR (400 MHz, DMSO) 6 10.51 (s, 2H), 8.00 (s, 2H), 7.54 (d, J = 8.0 Hz, 4H), 7.26 (d, J = 7.9 Hz, 4H), 6.26 (s, 1H), 5.77 (s, 2H), 2.34 (s, 6H). 13C NMR (101 MHz, DMSO) 6 162.8, 162.6, 140.1, 138.4, 132.5, 129.4, 126.0, 73.3, 21.0.
NCL196 (4’,4'-((1E,1’E)—((2-aminopyrimidine—4,6-diyl)bis(hydrazinyl y|idene))bis(methanylylidene))diphenol) ] A suspension of 2—amino—4,6-dihydrazinopyrimidine (70.4 mg, 0.454 mmol) and 4-hydroxybenzaldehyde (140.3 mg, 1.149 mmol, 2.53 eq.) in EtOH (3 mL) was heated at reflux for 16 h. The reaction e was cooled to ambient temperature before collecting the precipitate, washing with Et20 (25 mL), to afford the pyrimidine (91.4 mg, 55%) as an off-white powder. MP. 298 °C (Decomp.). 1H NMR (400 MHz, DMSO) 6 10.31 (s, 2H), 9.74 (s, 2H), 7.94 (s, 2H), 7.48 (d, J = 8.6 Hz, 4H), 6.83 (d, J = 8.6 Hz, 4H), 6.20 (s, 1H), 5.70 (s, 2H). 13C (101 MHz, DMSO)6162.7, 162.5, 158.3, 140.5, 127.7, 126.3, 115.7, 73.0.
EXAMPLE 2: Giardia Adherence Assay Aim. The aim of this study was to determine the anti-giardial activity of NCL099 and NCL812.
Methods. Giardia strain WB was grown until confluent (grown and maintained in TYl-S-33 medium with 10% foetal bovine serum). For the assay, media of a confluent culture was replaced with fresh 33 medium. Cultures were then cold shocked (on ice) for 40 minutes to detach trophozoites. The cell y of the cultures was adjusted to 1 x 106 cells/ml and 1 ml was added to each well of a 24 well plate already ning 1 ml of diluted compounds (see below). A coverslip was placed in the bottom of each well and the assay was incubated in an anaerobic environment (candle jar) for 2.5 hours at 37°C. After incubation the lips were removed, air-dried and stained with Diff-Quik (a Romanowski stain variant).
Coverslips were mounted onto glass slides using polymount. Images at 10x magnification were taken at 5 random locations per coverslip. Dotcount freeware was used to count the number of cells per image and this data was analysed using GraphPad Prism v6. Stock solutions of compounds were ed in DMSO at 25.6 mg/ml. Compounds were diluted 1:100 in 33 medium. A 1:2 serial dilution was then med in TYl-S-33 medium in 24 well plates.
Results. The results of this study are presented in Figures 2 to 3. Figure 2 shows the activity of NCL099 against Giardia duodenalis in vitro. A significant decrease in the number of adherent cells was observed at NCL099 concentrations of 11 pg/ml (P=0.0099), 38 ug/ml 01) and 128 pg/ml (P=<0.0001) compared to the control (Figure 2). An se in activity was seen as the concentration of NCL099 increased. Figure 3 shows the activity of NCL812 and metronidazole against Giardia duodenalis in vitro. A significant decreases in the number of nt trophozoites is seen for both metronidazole (P=0.0002) and NCL812 (P=<0.0001).
The samples were exposed for 5 hours not 2.5 hours.
Conclusion. This study demonstrates that NCL099 and NCL812 inhibit the ability of Giardia cells to adhere to a surface therefore limiting the ability of this pathogen to cause disease (as adherence is necessary to cause disease).
EXAMPLE 3: Resazurin Reduction Assay Aim. To determine the activity of NCL812 and NCL062 against Giardia duodena/is in vitro Methods. Giardia zoites were grown until ent. The media was replaced with fresh media and they were cold shocked for 40 minutes (as above). Cells were diluted to a concentration of ~ 500 000 cells/ml and 100 pl were added to each well of the assay plate (except media only control). The assay was incubated in an anaerobic environment (candle jar) for 42 hours at 37°C. AlamarblueT'V' was added to a tration of 10% and the samples incubated in an anaerobic environment for a further 6 hours. After incubation the absorbance of each sample was read at 570 and 630 nm. The percent reduction of resazurin (AlamarblueTM) was calculated and data was analysed with ad Prism v6 software. Assay set-up: the assay was med in 96 well plates in a total volume of 200 pl. 100 pl of NCL812 or NCL062 (concentration of 25.6 mg/ml in DMSO) or metronidazole (concentration 5 mg/ml in DMSO) stock was added to 9.9 ml of TYl-S-33 medium, then serially diluted 1:2 in the same medium. Cells were added as above.
Results. The results are shown in Figures 4 to 6. All three compounds tested (NCL812, NCL062 and metronidazole) showed a reduction in the metabolic activity of the trophozoites (indicated by a decreased percentage of reduction of resazurin). Both NCL compounds showed greater activity when compared to idazole.
Conclusion. Both NCL812 and NCL062 show inhibitory activity towards Giardia duodenalis trophozoites in vitro.
EXAMPLE 4: Erythrocyte ysis assay Aim. The aim of this study was to determine the in vitro ty of NCL812, NCL099 and NCL062 against mammalian cells.
Methods. Whole sheep blood was obtained from Thermofisher scientific. The red blood cells were separated from other blood ents via centrifugation at 1500 g for 10 s and washed with saline 3 times. Erythrocytes were diluted to a concentration of ~1x 101O cells/ml in saline. 50 pl of NCL compounds diluted in DMSO (see below) were added to 1.5 ml Eppendorf tubes and 500 pl of diluted red blood cells were added to each tube. Erythrocytes were incubated with compounds for 30 minutes at 37°C with gentle g (75 rpm). After incubation cells were placed on ice for 5 minutes then centrifuged at 1500 rpm for 10 minutes to pellet cells. The supernatant was d and serially diluted in saline. Absorbance of the atant and dilutions were recorded at 550 nm. Sample lysis was compared relative to cells Iysed 100% in distilled water and ed using GraphPad Prism v6 software.
Results. The results of this study are presented in Figure 7 (NCL062 tested from 1 to 128 pg/ml, NCL812 tested from 2 to 256 pg/ml, NCL099 tested from 8 to 1024 pg/ml).
Figure 7 shows the amount of erythrocyte lysis as a percentage of the positive l (100% Iysed blood cells in water) at various concentrations.
Conclusion. This study demonstrates that the tration required of each compound to cause a toxic effect in mammalian cells (erythrocytes) is much higher than the concentration required to effect protozoal cells (giardia). This study also demonstrates that NCL099 appears to have greater selectivity for bacterial and oal cells than mammalian cells when compared to NCL812 and NCL062.
EXAMPLE 5: Transmission Electron Microscopy Study Aim. To determine the effect that NCL812 has on the ultrastructure of Giardia duodenalis.
Methods. Giardia WB strain was grown until confluent (same as above) and old media was replaced with fresh media containing 6 pglml NCL812, 25 pg/ml metronidazole or 0.1% DMSO (control). Samples were incubated at 37°C for 1 hour (NCL treated) or 4 hours (Metronidazole and DMSO control) then cold shocked to detach trophozoites. Treated samples were centrifuged at 900 x g for 10 minutes and washed twice with cold . Final cell pellet was resuspended in pre-cooled fixative (1.25% gluteraldehyde, 4% paraformaldehyde in PBS with 4% sucrose, pH 7.2) and left overnight. Samples were post-fixed in 2% osmium tetroxide solution for 1 hour and dehydrated through a graded ethanol series (70 — 100%). Samples were embedded in epoxy resin and stained with uranyl acetate and lead citrate before viewing on an FEI Tecnai G2 Spirit Transmission Electron Microscope.
Results. The results of this study are shown in Figure 8. This figure shows the severe change in the ultrastructure of the NCL treated trophozoites (D-G) compared to the controls (A—C). Development of vacuoles and disintegration of the asmic membrane is observed.
Conclusion. NCL812 causes significant changes in to the ultrastructure of Giardia duodenalis.
EXAMPLE 6: ations of Compounds The following formulations were prepared using standard methods in the art.
Formulation A — Topical Formulation - PEG-based Gel with compounds of the invention 4.09 PEG 4000; 3.59 PEG 200; 0.6g ene glycol; 1.99 water; and 0.2049 of Compound (for example, ) PEG 4000, PEG 200 and propylene glycol were mixed and heated to 150 °C and until all solid crystals were dissolved. nd was added to water and sonicated for 30 minutes until fully suspended. The Compound solution and gel solutions were mixed and allowed to cool and solidify. Formulation A will likely demonstrate acceptable viscosity, ease of skin application, m suspension and consistent and fine texture.
Formulation B — Topical Formulation - PEG-based Gel with compounds of the invention 3.09 PEG 4000; 1.09 PEG 8000; 3.09 PEG 200; 1.09 propylene glycol; 1.99 water; and 0.2029 of Compound (for example, NCL099) PEG 4000, PEG 8000, PEG 200 and propylene glycol were mixed and heated to 150 oC and until all solid crystals were ved. Compound (for example, NCL099) was added to water and sonicated for 30 minutes until fully suspended. The nd solution and gel ons were mixed and allowed to cool and solidify. Formulation B demonstrated acceptable viscosity, ease of skin application, uniform suspension and consistent and fine e. ation C — Topical Formulation - PEG-based Gel with Compound-Soluplus 2.59 PEG 4000; 4.09 PEG 200; 2.59 propylene glycol; 1.09 water; and 1.89 solid dispersion of Compound-SoluPlus.
Soluplus was purchased from BASF (www.solup|us.com). Compound-SoluPlus was prepared using standard methods in the art. PEG 4000, PEG 200, Compound—SoluPlus and propylene glycol were mixed and heated to 150 °C and until all solid crystals were dissolve.
Water was added and then the solution was sonicated. The solution was allowed to cool and solidify. Formulation C demonstrated acceptable viscosity, ease of skin application, uniform suspension and consistent and fine texture. ation D — Tablet Formulation 30mg Calcium hydrogen phosphate dehydrate; 80mg Microcrystalline cellulose; 50mg Lactose; 8mg ypropyl methyl cellulose 1.5mg Talc 10mg of compound (for example NCL099) The excipients were weighed and mixed for 5 minutes. The mixture was fed into a feed hopper of a tablet press machine and the machine was operated ing to standard procedures in the art. Formulation D demonstrated acceptable tablet hardness, disintegration and frability. ation E — Oral Suspension 2.0 ml Glycerol; 1.5ml Absolute l; 600mg NCL812; and To 60ml Vehicle (Ora Sweet and Ora Plus, 1:1).
NCL 812 powder was sieved through a 75 pm sieve. 600 mg of sieved NCL 812 was mixed with 2.0 ml glycerol and 1.5 ml absolute ethanol. The mixture was placed in a mortar and manually milled until all NCL 812 was ded uniformly. The suspension was sonicated for 30 minutes. Vehicle (55 ml of Ora Sweet and Ora Plus mixture) was then added to the suspension and milled for another 10 minutes. Volume was made up with the Ora plus and Ora sweet mixture to 60 ml by transferring to a measuring cylinder ] Formulation E demonstrated acceptable sion and demonstrated acceptable short term stability.
Formulation F — Intramuscular Injection 20mg/ml Polyvinylpyrrolidone K30 (PVPK30); 0.09mg/ml NCL812; and 50ml water.
Two percent of w/v PVP K30 on was prepared by the addition of 1.0 g of PVP K30 to 50 ml of WHO water. The solution was then placed in a sonicator for 30 minutes to equilibrate and 4.5 mg of NCL 812 was added to the PVP solution and placed on an incubator shaker at a maximum speed of 10 rpm over a period of 24 hours, with controlled temperature of 25i1°C. Solution was transferred to 5 ml vials and checked for clarity, appearance, pH and short—term stability. The pH of solution was 7.25.
Formulation F demonstrated acceptable transparency and short term stability.
EXAMPLE 7: Release of NCL812 and NCL099 from Formulation B.
Aim: The objective of this study was to measure the release of NCL812 and NCL099 from Formulation B prepared in Example 6.
Method: Franz diffusion cells were ed to quantify the e rate of NCL 812 and NCL099 from its topical ations. Five millilitres of absolute ethanol, which was chosen as the desired release medium, was loaded into the receptor chamber. ature of the receptor fluid was kept constant, at 32i1°C using a water jacket. Acetyl cellulose membranes, with pore size of 0.45 pm (Pall Corporation) was selected and placed between donor and receptor chamber. Followed by that, a number of test samples (Formulation B) was loaded into the donor chamber. One millilitre of receptor fluid was collected at regular time intervals of 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours through the sampling port. One millilitre of fresh absolute l was immediately returned to the receptor chamber. UV-HPLC was utilized to analyse the t of the receptor fluids attained.
Results and Conclusion: Figure 9 presents the cumulative release of NCL812 and NCL099 over time. This study demonstrates that Formulation B provides an acceptable release profile for NCL812 and .
EXAMPLE 8: NMR Specroscopy Lists of Compounds NCL812, NCL001-NCL275 NMR Spectroscopy was med on compounds NCL812, NCL001-NCL275 using standard methods in the art. The lists of the NMR spectroscopy are presented in Table 3. 2133.2 8.9-03 8.0 ox .fm EN .E .NI in _. .NI NI .3 «.9 EN .3 "Iv Nm EN mm." 3 u .3 .NI EN EN EN .3 u .Em EN 738.2133 - 1.3 3 .3 .3 mm." E n .NI .3 m: Ev EN 9N." mm.» - «.3. E .13 .3 .E mag mg .3 .3 .fw E Ev .N1 3.9 - 3 fo n .EN EN E21389 n 30 89 5.9-3.219 8.x. .3 .N: .NI .93 93 .3 2, .w .AIN .3 E 13mm: .fm - .AE E 0.9 3 8.9 .3 2, .3 8.," 30 .3 Qw u .3 .3 n .13 .N: E. .3 8.9 fv B.» Em 8.» u $9 as .3 u m3 .3 .3 83 .13 as .NI 9E - w - .32» .EN .EN .3 .03 - mm.m 3.2 $9 .138.» .3 - u .52" 3 - Ev 9.» 93. .3 .3 .3 mm .1393 89 .3 - - NVN mm.» mag 33E. 213 .NI 3% .N: .32. .E 3w E w." .fm m: H .2133 _, _, mm.» E." w: .935 .33 .EN .30 .93 .EN u .. .3 u £9 3 .3 .EN .3 3 3 n .30 .3 .3 .13 a .3 - .3 .3 5.9-3.0 .NI .E .30 .3 .03 mg 30 .E u u 89 .3 n was N3 .3 8.3 mi. a .3 E u n n 1.35.2239338 13 8.3 9: .3 .w .m 9: mm.» a 2E w 3 8.» .sz .93 .3 .3 u 3% .N: mNNAOZéOOJOZ .32» N3 _. - .3 .3 .3 .322 - - - £9.33 i u .N1 - 3.9 9i m2 .52" :3 .3m .50 .30 j .3 .N: a: 8..\. .E 99 .3 83 No.» v3 m; n .3 _.
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N8 8.3 88 :33 :3 0:: :8 8.3 .AI: .2m 5.: 8.3 .3 8.3 .3 .3 .AI: 5.23 5.2N 8.3 5.:. .2IN 3:: 8.3 mm: 5.2: .NI .NI 5.2: .2Im .AIN .fm 5.2" .m .22: 5: 8.3 .m :3 8.3 3:3 .m .w .m 2:: .w .m .w .m .w .23 .2I: 5.2: 5.2: .3 8 3.3 .3 .3 .3 .AI: 5: u .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 5.2: 8.3 .2I: .3 .3 .3 5.: 3:3 2. 8.3 5.3 3:3 3.3 3:3 «N3 .3 .3 333 8.3 8.3 0:3 :33 3:3 3% .3 «:3 «:3 .3 .3 - .3 3% - .fm 5.2: 333 .21: .AIN 5: 5.: 8.3 5.2: .2IN 5.: 5.: .AIN 5.2m 5.2m mg 3% 8.3 5.2: .5: .AI: 8.3 8.3 8.: .m .m .m .w .m .w .w .m .f: .21: .m .m .w .m .m .21: .AI: 5: .m .m .m .2I: .AI: .AI: 21393.5: .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 8.8 3:: 8.: 8.: 8.: 5.:: N:.N: 8.: :m: mm: :3: 88.: mm: 8.: :0: 3.: 38: 8.: ::.: 8.: 8.: :32: 8.3: 5.22: 8.0: m m m m m n 3 m 3 m m m 3 m 3 m 3 3 m 3 w m m m 3 6.320 6820 6320 6320 6320 6320 6220 6320 6320 6320 6320 6320 6320 6320 6320 6320 60220 6320 6920 6320 6320 6320 6320 6320 6320 .NI22 .532 .NI22 5.23.3 .NI22 .NI22 .NI22 .NI22 .NI22 .32 .332 .NI22 .322 .NI22 .NIE .NI22 .NI2 .NI22 .NI22 3.222 .NI22 .32 .NI22 $222 3.222 .NI22 83 83 83 88 83 83 83 83 83 83 .3 83 83 83 83 83 83 :5 83 83 83 83 83 83 83 83 83 83 m2z 3222 "2222 .2IN 3222 322 m2z m222 3222 322 33.3 322 «2222 W222 E22 "2222 322 .3 322 "2222 «2222 3222 3222 322 «.222 m2z 3222 I: 2.2: I: .NI I: I: 2.2: 2.2: f: I: I: 5: 2.2: I: I: I: 2.: I: 8;: 2.2: I: I: 2.2: I: 2.: I: I: I: m QNOJOZ NNQJOZ mNogo mNOJOZ 000.202 50.202 NMOJOZ mmoqoz VMOJOZ 000.202 mmoqoz $6.00 wmogo 00040 030.5 3301.0 $5.2 wvoqo 2 Z 9.0.202 NvOJOZ 2 3.0402 Z 2 mwoqoz 030.52 02 Z 0.5402 omoqoz Substitute Sheet (Rule 26) RO/AU .AIN 3.3 AI: .NI .AIN No.3 :Im . .w NI :3 .NI .33 .NI n 4: 3 5 3.: :33 3.: i: u .3 u .NI u .3 5 5 AI: 5 mm: .3 .3 3.: .3 03m .NI n 30.: AI: 5.: 33.: AI: 0.N AI: .AIN .m 33.: 5.3 .AI: .NI .23 .AIN .NI AI: 5.: .NI 55» .NI .NI 3.: Em n .NI .25: 3 .m 3: ::.: 3.: 3.: 5 u n d3 AIN .23 .3 3.: u u 5.: .53 .NI Em u 5 .AIN .3 5 .3 5 .3 5 .33 EN .3 - AI: MIN :3 5:..." .3 0.: a Em .3 mm: .NI Em .3 :3: AIM in mm: .NI 03.: 33: .m .m u .3 :3: 0.: .3 :3: .AI: 03 .33 .AI: .AIN 5 .3 00.: .AIN .3 0.5 AI: .3 n - .AI: 03m .w .3 n .AIN :3 03m mvd AI: .AIN 00.3 $3 .23 .NI :3: 53 .NI EN .3 .NI .m .: 8.: .: .3 033 3.: .AIV .AIv 5.:. 3.: .AIN AI: .03 .NI - 3.: .AIN .33 .AIN mm: 00.: 0.: u 53 u 9.: .NI .NI .3 n n 3.: .NI n .33 .NI 5.3 5 .NI 5 .NI u .NI .3 AI: .3 N3 0.3 .AIN 3.3 .3 .3 mm: 5 0.: m5 .3 m3: .AIN 3 .NI 8.: 3.: u n 5.5V ::.: u u .NI n .m n 5 5 :3: mm: .25: u 5 5 8.3:: .3 mm: - 5 :3 0.3 5 .3 .3 NI .3 5.: «3 05.: .AI: .3 8.: u .AI: .3 .3 mm: .3 u .fm mm: mm: 3.: AI: .AIN .3 3:: 3:: 5.3 :N: .3 .NI 3:: u 3: .53 .3 .NI m3: ::.: 5 .NI 53 .AI: - 5 u .3 3.3.: .AIv .53 .NI .AIN .AIN .3 .AIN 8.: 30.0 3.: .AI: .3 8.3 05.: 3 .AIN 5 .AIN 3: $3 33.: .3 333 u .NI .NI n u .3: .w .NI .NI .AIN .m :3: .AI: .5: .AI: AIN .w 3.: .AIN 5 .w .AIN .3 :3 u .53 :3 .3 .3 3.: 0.3 .3 0:3 5 - :.m .NI .NI 33 .NI mm: u n .33 .w Em .NI .m 03.: 5.3 .m .NI .3 5 .m 0.: E: .3 .3 3.5. 0.3 2.3 5.3 0; .3 .3 .NI .._3 :03 E: 5.: .33 3: 3 .3 .m 05.: n u u n .AI: .AI: u u n 95m 5 .AI: 0% 3.: 5.3 .AIN .AIN .AIN 5 5 5 .25: 3% fa 8.5 EN 33.3 .23 5 n .3 .3 .3 .53 .3 .53 .3 .3 .3 .NI .NI 5 .AI: 23 .3 .NI .NI m3: .NI .2IN 3.: AI: AI: .3 5.: .: 0:3 mm: 03.: 3:: ::.: mm: 3.: .m 3.5.: 35.: 3.: N3 3; .8: 3 .3: :3 3.: .AIm 33.: .m .m .w .w u n u u .w .AI: n .AI: 5: .25: .23 .AI: I: .5: 5: 5: n 5 5 5 5 .53 - 33 5 533 .3 .53 5: .fm .3 .3 .3 2:3 .3 .3 - .3 .3 .3 5.3 .3 .3 .3 .3 .3 .AIV 8. .3 .3 8.: .0 3:5 .3 .NI 5:5 03.: :33 mm: : mm: .AI: 2.3 m; 50.3 8.: «3.: .NI ::.: :3 9.3 :23 3:: 03m $5 33 8.3 .?IN .AIN .AIN AI: .AIv 3.: AI: 5.: .AI: AI: n .AI: AI: .AI: .03 5.: .AI: .fm .: 5 .m .m .AI: .AI: .AI: .AI: 5: 5: .w .m u .m .w .m AI: :3: .m .m .m .5 .m .m .3 .53 .3 .3 .3 .33 .3 .3 .3 .3 .3 .3 .33 03 .33 .33 .3 .3 - .3 33 .33 .3 .3 .3 .3 330: 8.: 33.: :2: 3.0: mm? 8.0: 30.0.. mm? 8.0: E: 33.: 8.: 3.: 0mm: m3: 030: :33 3.3 NEW 5.3: AIm 3.: :55 33.0: 333 8.3 m 3 3 w 3 0 m m 0 3 5 m 3 m m .3 m 0 3 3 m m n m .3 m m 8320 8.320 6320 6320 6.35 6320 6m2o 6320 632a 6325. 8320 8920 6320 6329 6320 6320 6320 8m20 6w2o 62.5 8m2a N33AI: 6320 6320 6320 6320 6320 .332 .NI2 .NI2 .NI2 .NI2 .NI2 .NI2 .NI2 .NI2 .332 .NI2 .NI_2 .NI_2 .NI3 .NI2 .NI2 .NI_2 .NI2 .NI2 .NI2 .532 .NI .332 .NI2 .NI_2 .332 .NI2 003 003 003 003 003 003 003 003 oo?mma7wvw 503 003 003 003 003 003 003 003 003 003 003 003 3:u 003 003 003 003 003 5.50. «22 3.22 322 322 322 322 322 322 .w mLmNI: ":22 3.22 1.22 322 322 322 :22 322 322 «.22 m2z .3 322 E22 «22 322 322 .3 I: I: I: I: I: I: I: I: s .m I: I: I: I: I: I: I: I: I: I: I: .33 I: I: T: 53 I: I: :3 $0402 Nmmjoz mmoqoz $01.02 mmoqoz mmOAOZ wmogoz wmnjoz 9.3402 00302 50402 NQOJOZ mmoqoz vmogoz @3302 ©0302 :30402 wmoqoz mmo?uz 05402 E302 quoqoz whom—OZ 35.62 mncgoz 3.5.30 Substitute Sheet (Rule 26) RO/AU . . . . n n N1 0 0 01 .2E 010 . . 00.0 10 0.0 0 3 3 . . - . . 00.0 110 N1 0 01 3 n 00 u 0 00.0 0 . 0 . 0.0 0 . . 3 210 0 00.0 E 010 .210 .3 u u 00.0 0 . .3 .
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Aim: The objective of this study was to determine the activity of NCL219, and NCL231 — NCL247 against Giardia duodenalis in vitro using the Resazurin Reduction Assay.
Methods: Giardia trophozoites were grown until confluent. The media was replaced with fresh media and cold shocked for 40 minutes. Compounds were prepared in DMSO and serially diluted 2-fold in DMSO starting at with a 1/100 dilution of the stock (e.g. 128 mg/ml stock starting on would be 128 pg/ml). 2 pl of dilutions were added to the appropriate wells and 198 ul of TYl—S-33 media added to each well. Cells were d to a concentration of ~ 500 000 cells/ml and 100 pl were added to each well of the assay plate (except media only control). The assay was incubated in an anaerobic environment (candle jar) for 5 hours at 37°C.The media was removed and replaced with 100 pl of warm PBS then AlamarblueTM added to a concentration of 10%. The samples were incubated in an anaerobic nment until colour development. After incubation, the absorbance of each sample was read at 570 and 630 nm. The percent reduction of resazurin (AlamarblueTM) was calculated (using the formula below) and data was analysed with GraphPad Prism v6 software. The formula used to calculate t reduction of Alamarblue was ((oni630 x A570) — (oni570 x A530))/((Ered570 x C630)-(Ered x C570» x 100, Where: oni630 = 34798, oni570 = 80586, A570 = absorbance at 570nm, A630 = absorbance at 630 nm, Ered570 = 155677, Ered630 = 5494, 0630 = ance of negative l well at 630 nm and C570 = absorbance of negative control well at 570 nm.
] Results and Conclusions: Three of the compounds tested in this assay showed excellent inhibitory activity towards Giardia duodenalis in vitro, NCL245 (9.6 uM), NCL246 (5.4 uM) and NCL219 (1.03 uM). The results are presented in Table 4.
Table 4 S. aureus GiardiaW Giardia [Stock] NCL code ATCC 29213 B W3 (m9lml) (ugImI) (ug/ml) (uM) NCL234 64-00 _" "246 "- *IC50 could not be calculated "1 repeat only |C50 after 5 hours, MIC after 24 hours, NC — not converged EXAMPLE 10: Anti-trypanosomatid activity of NCL analogues Background: Trypanosomatids cause significant human morbidity and ity with an estimated 1.3 million new cases per year resulting in ~30 000 deaths occurring due to Leishmania sp. alone. In addition to this osomatids, such as Trypanosoma brucei (endemic to Africa), cause significant morbidity and ity to humans (upto 66 million people affected) as well as significant losses in the livestock industry (known as nagana). Currently the chemotherapy available for these organisms is limited and has unwanted toxic side effects. In this study, we looked at the in vitro efficacy of 20 chemical analogues from the NCL series (see Table 5 for details) against the procyclic stage of T. brucei and the promastigote stage of Leishmania donovani. Analogues that showed promising in vitro ty against either of the parasites were tested in vitro for selectivity against a mouse macrophage cell line (ATCC RAW Aim: The objective of this study was to: (1) evaluate the in vitro antiparasitic activity of 20 structurally related aminoguanidines (from the NCL series) against T. brucei and L. donovani; and (2) determine the selectivity of these compounds for tes over mammalian cell.
Methods: Antimicrobial agents (Table 5) were all dissolved in DMSO to a final concentration of 10 mM. Pentamidine (Sigma) was used as a positive l and prepared as the NCL compounds Table 5.
Scaffold 1 Scaffold 2 Scaffold 3 R. R. R /\)\~ H H H H H ,N /N. / ‘ N 'N in YA,2\ ". " :f\ "3‘ "7 Rzi " 7:! i. 'NH2 ~‘.~ 7 Hi If N i V v L: NH Compound R R CompOUNd R Compound R R’ MNCL195 47H, mom H W, W"CU-"’7 5‘0" NCL042 H 2—CF3 NCLDZB ZaOCHg H NCL201 4-N(CH3)2 NCL052 H 3—Ci NCL062 4-CI CH3 NCL191 CH3 4-Cli NCL099 4-C(CH3)3 H NCL231 CH3 4—C(CH3)3 NCL113 4-N(CH3)2 H NCL166 4-SCF3 H 2-OH ’ 4- NCL171 H N(CH3)2 NCL219 4-C(CH3)3 CH3 NCL812 4-CI H L. donovani Screening. lic promastigotes from exponentially growing cultures maintained in DME-L+ Bob additions were used for all assays. Compounds were initially screened for activity at 10 pM. Compounds were d in culture media to a final volume of 10 pM in 96 well plates. Promastigotes were diluted to a density of ~8 x105 cells/ml then added to the assay plate resulting in a final cell density of 4 x 105 cells/ ml. in 96 well . Cells were incubated for 96 hrs at 27°C before the addition of Alamarblue (thermofisher).
Fluorescence was read at excitation 530nm and Emission 590nm. Compounds that showed inhibitory activity at 10 pM were further igated to determine |Cso values. Compounds were ly diluted in thirds, in a 96 well plate, in cell growth media so that concentrations ranged from 0.005 to 10 pM and promastigotes added to a final concentration of 1 X 106 cells/ml. Cells were incubated at 27°C for 72 hours before the addition of alamar blue. scence was ed as above.
T. brucei screening. Procyclic promastigotes from exponentially growing cells maintained SDM-79 medium were used in all . Compounds were initially screened at 10 pM for activity. Compounds were diluted in culture media to a concentration of 20 pM and added to a 96 well plate, after on of promastigotes (final concentration 4 x 105 cells/ml) compound concentration was 10 pM. Cells were incubated for 48 hrs at 27°C before the addition of alamar blue and fluorescence measurement as described above. Compounds that showed inhibition at 10 pM were further characterised to determine le0 values. Compounds were serially diluted in thirds in culture media resulting in final trations ranging from 0.004 — 10 pM. Promastigotes were added at a final concentration of 4 x 105 cells/ml. Cells were ted at 27°C for 48 hours before addition of alamar blue. In addition promastigotes, at a concentration of 8 x105 were exposed to NCL026 for 1.5 hours before removal of the drug via centrifugation at 5000 rpm for 7 minutes and resuspension of cells in culture media. Cells were incubated for 96 hours at 27°C and observed daily for metabolic activity (alamar blue assay) and morphological changes. A l culture was d to DMSO instead of NCL026.
Cell toxicity assays. Mouse macrophages (RAW 264.7) were grown in RPM|1640 media supplemented with L-glutamine and 10% foetal calf serum. Cells were trypsanised when 80% confluent and subcultured every 3-4 days. For cytotoxicity assays cells were diluted to a final cell concentration of 2x104 cells/ml and 198 pl added to each well of a 96 well plate. Cells were incubated in a humidified incubator for 2 hours at 37°C 5% C02 before the addition of NCL compounds (2 ul/ well, previously diluted in DMSO). Campothecin, triton X and DMSO only were used as controls. Cells were exposed to the compounds for 24 hours. The metabolic activity of the cells was determined using the WST-1 assay system (Roche Life Science). The supernatant was d, 100 pl of PBS with 10% WST-1 was added to each well and incubated for 1 hr before reading absorbance at 450nm. The selectivity index of the compounds was determined by dividing the IC50 of hages by the IC50 against parasites. IC50 was determined via graphpad prism software. ] s: Robenidine and 19 structural analogues were screened for activity against the lic promastigote stage of L. donovani and T. brucei at 10 uM. Of the compounds tested 70% showed a 290% reduction of metabolic activity in L. donovani while % showed a similar reduction of metabolic activity in T. brucei (see Figure 10). The procyclic stage of T. brucei and the tigote stage of L. donovani were exposed to the nds for 48 or 96 hrs respectively before the effect was measured using a resazurin dye. Assays were repeated in cate. P = pentamidine. Error 1 SD.
Of those compounds active against L. donovani NCL026, NCL028, NCL041, NCL042, NCL062, , NCL195, NCL201, NCL219 and NCL246 had the greatest activity inhibiting the parasite 100%. Against T. brucei NCL026, NCL062, and NCL246 had the greatest inhibitory effect. NCL026, NCL062 and NCL246 were very effective t both species of parasites. Further investigation of a selection of compounds that had activity against the parasites was completed to determine the |C50 values. The leO value was determined for NCL028, NCL099, NCL166, , NCL245, NCL246 and NCL812 against L. ni. The IC50 ranged from 0.37 uM (NCL028) to 6.48 uM (NCL245 and NCL246). The IC50 value was determined against T. brucei with the 6 most effective analogues NCL024, NCL026, NCL062, NCL171, NCL195 and NCL246. Of these analogues NCL026, NCL171 and NCL195 were the most effective with |C50 values of 1.7, 1.4 and 1.5 pM respectively. The highest |C50 value determined was 4.2 uM for NCL246. A recovery assay to determine the y of T. brucei to recover after a short exposure to NCL026 was performed. After 1.5 hrs of exposure to the for select periods of time to determine the Gl50 or |C50. The selectivity index (SI) was determined by dividing the GISO of macrophages by the ICSO of parasites. An SI 210 is considered ive for the parasite. Assays were repeated in triplicate. Error 1 SD. Based on this assay the selectivity of the compounds ranged from 0.57 to 27.9. It is generally considered that a selectivity index <10 is relatively unselective while a selectivity 10 is considered selective for the parasite.
Based on this convention only one nd (NCL171) could be considered relatively selective for T. brucei while 4 compounds were highly selective for L. donovani in vitro (NCL028, NCL 099, NCL113 and NCL219).
Table 6 T. brucei L. donovani Compound G|50 macrophage (uM) |C50 (uM) SI |C50(pM) NCL 024 .79 3.351011 3.79 NCL 026 9.601099 1.681063 5.71 2.51013 NCL 028 81012.76 02910.05 NCL 062 7.151127 83 1.75 NCL 099 7.661056 0.371004 20.7 NCL 113 12.901349 09210.06 NCL 166 9.461005 32311.00 NCL 171 361 1.371003 9.14 NCL 195 5.781033 1.461076 3.79 NCL 201 122812.06 2.921022 4.23 NCL 219 192613.77 0.801010 24.08 NCL 245 3.71071 7.171205 0.57 NCL 246 13.831007 4.181037 3.31 67212.99 2.06 NCL 812 14.851134 2.91024 5.12 Conclusion. This study demonstrated that several of the compounds tested showed high inhibitory activity against either L. donovani or T. brucei in vitro. Based on the in vitro selectivity index, NCL171 appears to be the most promising against T. brucei while , NCL099 and NCL219 appearto be the most ing against L. donovani.
EXAMPLE 11: The physicochemical and metabolic properties of NCL026, NCL028, , NCL171, NCL177, , NCL217, NCL259 and NCL812.
] Aim: The ive of this study was to evaluate the physicochemical and lic properties of NCL026, NCL028, NCL099, NCL171, , NCL195, NCL217, NCL259 and NCL812.
The ochemical and metabolic characteristics of the nine compounds were assessed using a combination of in silico and experimental techniques and the results have been summarised in Figure 11.
Calculated physicochemical parameters for each compound were generally within the limits normally associated with compounds having "drug-like" properties. The polar surface area values of NCL026 and NCL171 are however, approaching the upper limit recommended for good membrane permeability, reflecting the relatively high number of heteroatoms within these two structures. All of the compounds demonstrated low c lities under neutral pH conditions, except for NCL259 which was more moderate. Most of the compounds showed greater solubility under acidic conditions (pH 2) suggesting an increase in ionisation at low pH. Measured partition coefficient values were relatively high at pH 7.4, with LogD7.4 values ranging from 3.6 to >53 LogD values were lower under acidic conditions (pH 3), however would still be considered to be moderate to high (2.8 to 4.9). The ed pH dependent solubility and partition coefficient results are consistent with the basic characteristics of the compounds predicted by their structures. The metabolic stability of the nine nds were evaluated in both human and mouse liver microsomes. Five of the compounds, NCL026, NCL177, NCL195, NCL259 and NCL812, showed low rates of degradation in both species of liver microsomes (EH values <0.3). NCL099, NCL171 and NCL217 showed intermediate to high rates of degradation (EH values 0.49 to 0.88) with degradation rates for each compound being broadly able between species. NCL028 showed a low rate of degradation in human liver microsomes and a high rate of degradation in mouse liver microsomes which may suggest a significant difference in metabolism between species for this compound. There was no able degradation of any of the nds in control (non-cofactor) lncubations in either species suggesting that there was no major cofactor independent metabolism contributing to their overall rates of metabolism.
Experimental Methods Calculated physicochemical parameters using ChemAxon JChem re tical physicochemical values for each compound were calculated using the ChemAxon chemistry cartridge via JChem for Excel software. Parameters calculated and a brief explanation of their relevance is given below.
] Molecular Weight (MW): Ideally, MW should be less than 500 for good membrane permeability.
Polar Surface Area (PSA): Calculated using a simplified 2-dimensional ing approach, which has been validated against a more sophisticated 3-dimensional modelling strategy. The value has been ated at pH =7.4, which takes ionisation of the molecule into account. It is usually ed that PSA values of less than approximately 120 A2 will e acceptable oral drug absorption and membrane permeability.
Freely Rotating Bonds: Number of single bonds that are not in a ring or constrained system and are not bound to a hydrogen atom. FRB should be less than or equal to for good membrane permeability (See D. Veber et al, J. Med. Chem. 2002, 45, 2615-2623).
H Bond Donor I Acceptors: Number of hydrogen bond donors and acceptors gives an indication of the en bonding capacity of the molecule which is inversely related to membrane permeability. Ideally, the number of H-Bond donors should be less than 5 and the number of H-Bond ors should be less than 10. pKa: Basic physicochemical measure of the acidity of a compound. In the context of drug development, the values themselves only indicate whether ionisation is likely to be relevant at physiological conditions.
Solubility Estimates using Nephelometry Compound in DMSO was spiked into either pH 6.5 phosphate buffer or 0.01 M HCI (approx. pH 2.0) with the final DMSO concentration being 1%. Samples were then analysed via Nephelometry to determine a solubility range. (See C. D. Bevan and R. S. Lloyd, Anal.
Chem. 2000, 72, 1781-1787).
LogD Measurement Partition coefficient values (LogD) of the test compounds were estimated by correlation of their chromatographic retention properties against the characteristics of a series of standard compounds with known partition coefficient values. The method employed is a nt HPLC based derivation of the method developed by Lombardo (See F. Lombardo et al, J. Med. Chem. 2001, 44, 497).
Microsomal Stability Incubation methods: The metabolic stability assay was performed by incubating each test compound (at 1 uM) with human and mouse liver microsomes (Xenotech, Lot# 1210057 and 1310211, respectively) at 37°C and 0.4 mg/mL protein concentration. The metabolic reaction was initiated by the addition of an NADPH-regenerating system (i.e. NADPH is the or required for CYP450-mediated metabolism) and quenched at various time points over a 60 minute incubation period by the addition of acetonitrile containing diazepam as internal standard. l samples ining no NADPH) were included (and quenched at 2, and 60 minutes) to monitor for potential degradation in the absence of cofactor. Analytical conditions: Instrument: Waters Micromass Xevo G2 QTOF coupled to a Waters Acquity UPLC; Detection: Positive electrospray ionisation under MSE mode; Cone Voltage 30 V; Column: Ascentis Express Amide column (50 x 2.1 mm, 2.7 pm); LC conditions: Gradient cycle time: 4 minutes; Injection volume: 5 pL; Flow rate: 0.4 mL/min; Mobile phase: Acetonitrile-water gradient with 0.05% formic acid lite; Identification: A metabolite screen was not included in this study, however, since data was acquired using MSE mode, which allows for the simultaneous acquisition of low and high collision energy MS spectra, a post-hoc lite search may be conducted at a later date if warranted.
Calculations: Test compound tration versus time data were fitted to an exponential decay function to determine the first-order rate constant for substrate depletion. In cases where clear deviation from first-order kinetics was evident, only the initial linear portion of the profile was ed to determine the degradation rate nt (k). Using rd methods in the art, each substrate ion rate constant was then used to ate: [1] a degradation half-life, [2] an in vitro intrinsic clearance value (CLint, in vitro); [3] a predicted in vivo hepatic intrinsic clearance value (CLim); [4] a predicted in vivo blood clearance value (CLbIood); and [5] a ted in vivo hepatic extraction ratio (EH). The following scaling parameters were assumed in the above calculations (Table 7).
Table 7 Microsomal protein Hepatic blood flow [0) : liverfk bod wei-ht ’mzf: liver mass leminutefk- bod wei-ht Human a 25.? 32 20.? Mouse 3 54.9 47 120 3 Ring et Ill. [20 11]) Journa! OJ" ceurfcai Sciences, 'l [1024090441 '1 D.
Predictions of in vivo hepatic extraction ratios: The microsome-predicted hepatic extraction ratios (EH) ed based on the relative rates of test nd ation in vitro, were used to classify compounds as low (< 0.3), intermediate (0.3 — 0.7), high (0.7 — 0.95) or very high (> 0.95) extraction compounds.
Results: The physicochemical and metabolic characteristics of the nine compounds were assessed using a combination of in silico and experimental techniques and the results have been summarised in Figure 11.
EXAMPLE 12: Exposure of NCL026, NCL195, NCL259 and NCL812 in male Swiss outbred mice following IV administration Aim: The objective of this study was to evaluate the systemic exposure of , NCL195, NCL259 and NCL812 in male Swiss outbred mice after N administration at 5 mg/kg.
Methods: The systemic exposures of NCL026, NCL195, NCL259 and NCL812 were studied in nonfasted male Swiss outbred mice weighing 26.2 — 32.1 g. Mice had access to food and water ad m throughout the pre- and post-dose sampling period. Each compound was administered |V via a bolus injection into the tail vein (vehicle 20% (v/v) DMSO in PEG400, 1 mL/kg dose volume, n=8 mice per compound). ing administration, blood s were collected at 5, 15, 30, 120, 240 and 480 min postdose (n = 2 mice per time point for each compound). A maximum of two samples wereobtained from each mouse, with samples being taken either via submandibular bleed(approximately 120 pL; conscious sampling) or terminal cardiac puncture (0.6 mL; while mice were anaesthetised using inhaled lsoflurane). No urine samples were collected as mice were housed in bedded cages during the study. Blood was collected directly into polypropylene Eppendorf tubes containing heparin as anticoagulant, and stabilisation cocktail (containing Complete® (a protease tor cocktail with EDTA) and ium fluoride) to se the potential for ex vivo degradation of the test compounds in plasma samples. Once collected, blood samples were centrifuged immediately, supernatant plasma was removed, and stored at -80°C until analysis by LC—MS using methods standard in the art.
] Each compound was administered in a vehicle composed of 20% (v/v) DMSO in PEG400. Formulations were prepared by dissolving the compounds in DMSO prior to addition of PEG400. Formulations were not filtered prior to dosing and were administered to mice within 2.5 h of preparation. The average measured concentration of each compound in aliquots (n=2) of their respective formulations was 4.58, 4.31, 5.26 and 5.25 mg/mL for NCL026, NCL195, NCL259 and , respectively. The dose administered to each mouse was calculated on the basis of the measured concentration in the IV formulation, the dose volume and individual mouse body weight. Plasma concentration versus time data were analysed using non- compartmental methods (WinNonIin Version 6.3.0.395). Standard calculations for each pharmacokinetic parameter were calculated using standard s in the art.
One mouse dosed with NCL812 exhibited abnormal behaviour (frantic, hyperactive) commencing a few minutes after dosing; this mouse was anaesthetised and blood was collected at 15 min post-dose. No other animals in this study appeared to exhibit any adverse reactions or compound-related side effects. There was evidence of haemolysis observed in plasma samples however this is likely to be attributable to the solvents used in the IV formulations (20% (v/v) DMSO in PEG400) which were required because of the limited solubility of the test nds in aqueous ation vehicles.
Results: The plasma concentration versus time profiles for NCL026, NCL195, CL259 and NCL812 are shown in Figure 12. The cokinetic ters are presented in Table 8. All compounds ted moderate-to-long nt terminal ation half-lives.
Table 8 —NCLoza NCL195 NCL259 NCL812 «seem:— Apparent twfh] 2.4 8.2 h Plasma CL [leminl‘kg] 1.600 16. 3 56.{i AUCoan "1HM} 12. 5 2?.9b a Plasma concentration at time zero could not be determined by near regression of the ?rst two measurements. and was therefore set to the ?rst observed measurement. As such, AU‘C from U to 5 min {and therefore AUCQMJ will be underestimated and ters calculated based on AUCn.m:are approximations only.
Terminal elimination phase was not well de?ned. value is an approximation only.
E 13: Exposure of NCL195 in male Swiss outbred mice following IP administration.
Aim: The objective of this study was to obtain a preliminary indication of the plasma exposure of NCL195 following lP administration at a target close of 50 mg/kg.
Methods: The formulation was prepared by dissolving solid NCL195 in DMSO (to % (v/v) of the final volume) before adding PEG400, yielding a clear yellow solution that was dosed to mice within 30 minutes of preparation. The measured tration of NCL195 in the final formulation was 21.9 mg/mL, resulting in a mean administered dose of 43 mg/kg. Following administration, blood samples were collected up to 24 h post-dose (n = 2 mice per time point). A maximum of two samples were obtained from each mouse, with samples being taken either via submandibular bleed (approximately 120 uL; conscious sampling) or al cardiac puncture (0.6 mL; while mice were anaesthetised using inhaled rane). No urine samples were collected as mice were housed in bedded cages during the study. Blood was collected directly into polypropylene Eppendorf tubes containing heparin as anticoagulant and stabilisation cocktail (containing Complete® (a protease inhibitor cocktail), potassium fluoride and EDTA) to se the potential for ex vivo degradation of NCL195 in blood/plasma samples. Once collected, blood samples were centrifuged immediately, supernatant plasma was removed, and stored in —20°C until analysis by LCMS using standard methods in the art.
Results: No adverse reactions or compound-related side effects were ed in any of the mice following IP administration of NCL195 at a dose of 43 mg/kg. The plasma concentration-time profile (Figure 13) indicates that NCL195 was rapidly absorbed after dosing.
For the duration of the initial 7.5 h post-dose period, plasma concentrations remained above 3 - 4 pg/mL, r concentrations fell to 0.2 - 0.5 ug/mL between 7.5 and 24 h post-dose.
Assuming that a 2-fold increase in dose would result in a proportional increase in NCL195 exposure, the present data suggests that IP administration of NCL195 at 100 mg/kg (as a solution formulation) would result in at least 7.5 hours of exposure at a plasma concentration >8 ug/mL.
EXAMPLE 14: Activty of NCL Analogues againt Trypanosoma cruzi Background: Chagas’ disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite osoma cruzi (T.
. T. cruzi is transmitted when the infected faeces of the triatomine vector are inoculated through a bite site or through an intact mucous membrane of the ian host. Vectorborne ission is d to areas of North America, Central America, and South America. Both in c and in nonendemic areas, other infection routes include usion, organ and bone marrow transplantation, and ital transmission. Outbreaks uted to contaminated food or drink have been reported in northern South America, where transmission cycles involving wild vector populations and mammalian reservoir hosts are prominent. Infection is lifelong in the absence of effective treatment. The most important consequence of T. cruzi ion is cardiomyopathy, which occurs in 20 to 30% of infected persons. The World Health Organisation estimates that in 2015 about 6 million to 7 million people are infected worldwide, mostly in Latin There are only two drugs, the nitrofuran nifurtimox and the nitroimidazole benznidazole, with established efficacy t T. cruzi ion. However, each of these agents have significant tions in effectiveness and .
] In patients with acute Chagas’ disease and in those with early congenital Chagas’ disease, both benznidazole and nifurtimox reduce the severity of symptoms, shorten the clinical course of illness, and reduce the duration of parasitaemia; but cure rates in the acute phase are only in the order of 80 to 90%.
Studies of benznidazole involving children with chronic T. cruzi infection have revealed cure rates of only around 60%, on the basis of conversion to negative gic test results 3 to 4 years after treatment.
Nifurtimox use is associated with gastrointestinal side effects (anorexia, weight loss, nausea, and vomiting) in up to 70% of patients. Neurologic toxic effects include irritability, insomnia, disorientation, and tremors. Rare but more serious side effects include paraesthesias, polyneuropathy, and peripheral neuritis.
Benznidazole use is frequently associated with dermatological adverse effects, usually mild rashes that respond to antihistamines. However, severe or exfoliative dermatitis or dermatitis associated with fever and lymphadenopathy prompt immediate interruption of treatment. A dose-dependent peripheral neuropathy occurring late in the course of therapy necessitates ate cessation of treatment. Although bone marrow suppression is rare its occurrence prompts immediate uption of treatment.
The absence of safe and effective treatments has led to Chagas ’ disease being classified as a neglected parasitic infection with major public health implications. The global cost of Chagas ’ disease has been estimated at more than US$7billion (Lee, B. Y., K. M. Bacon, M.
E. Bottazzi and P. J. Hotez (2013). "Global economic burden of Chagas disease: a computational simulation " The Lancet ious Diseases 13(4): 342-348) and there remains a ate and continuing need to identify and develop improved treatments.
Aim and Methods: In an endeavour to identify new agents for the treatment of Chagas’ disease, the biological activity of robenidine and 79 ues against soma cruzi was assessed in an in vitro screening assay according to the methods described by Keenan et al (Keenan, M., M. J. Abbott, P. W. Alexander, T. Armstrong, W. M. Best, B. , A. Botero, J. H. Chaplin, S. A. Charman, E. Chatelain, T. W. von Geldern, M. Kerfoot, A. Khong, T. Nguyen, J. D. McManus, J. Morizzi, E. Ryan, |. le, R. A. Thompson, 8. Z. Wang and K. L. White (2012). "Analogues of fenarimol are potent inhibitors of Trypanosoma cruzi and are efficacious in a murine model of Chagas disease." Journal of medicinal chemistm 55(9): 4189— 4204), Buckner and associates (Buckner, F. 8., C. L. Verlinde, A. C. La Flamme and W. C. Van Voorhis (1996). "Efficient technique for ing drugs for activity against Trypanosoma cruzi using parasites expressing beta-galactosidase. Antimicrobial Agents and Chemotherapy 40(11): 2592-2597) and by Van Voorhis and Eisen (Van Voorhis, W. C. and H. Eisen (1989).
"Fl—160. A surface antigen of Trypanosoma cruzi that mimics mammalian nervous tissue." M l of Experimental Medicine 169(3): 2).
In vitro T. cruzi Assay for ination of |C50.
The T. cruzi assay uses Tulahuen trypomastigotes expressing the 13- galactosidase gene. The parasites were maintained in vitro by serial passage in L6 cells. y, L6 cells were plated into 96 well, flat-bottom tissue culture plates and ted at 37°C in 5% C02 for 24 h to allow cells to adhere. T. cruzi trypomastigotes were then added at a licity of infection of 3, and plates were incubated for a further 48 h to allow infection to establish. All steps were carried out using RPMI media 1640 (without phenol red) supplemented with 10% Foetal Bovine Serum (FBS, Bovogen). Extracellular trypomastigotes were then d and NCL compounds were added in seven-point serial dilutions performed in cate. Benznidazole (Epichem Pty Ltd.) was included as a control. After 96 h of incubation with the compounds, the colorimetric agent, chlorophenol red-fl-D-galactopyranoside (CPRG, Roche) was added with 0.3% v/v Nonidet P-40. After 4-6 h, a colour change ing catabolisation of the reagent by viable T. cruzi was observed and absorbance was read at 530 nm using a Dynex microplate reader. The % inhibition was calculated by the following equation: %inhibition = 100 - [(T. cruzi with compound - compound only)/(T. cruzi only - media only)] X 100. For each compound, % inhibition values were used to generate a standard curve from which the IC50 was ated.
Each assay was performed at least twice, and the average was used.
Results: The value of the ICSO of 80 NCL compounds is presented in Table 9.
Table 9 aCtIVIt NCL024 Compound NCL080 NCLO36 NCLO41 NCL016 NCL812 V NCL086 NCL020 NCL011 V_\_\ _\_\ NCL052 NCL073 NCLOOS NCLO75 15 NCLO45 29 NCL018 NCL021 NCLO46 32 NCL001 NCL037 NCL074 33 NCLOOB NCL038 NCL002 38 NCL008 NCL079 >10 ] Conclusion: Notably, 6 compounds had an |C50 of less than 10 uM while 30 compounds had leo values less than or equal to 20 pM. The NCL series provides a rich source of agents with activity against Trypanosoma cruzi.
Claims (19)
1. Use of a compound chosen from the list comprising: NCL024 2,2'-bis[(4-cyanophenyl)methylene] carbonimidic dihydrazide hydrochloride NCL114 2,2'-bis[(3,5-dichlorophenyl)methylene]carbonimidic dihydrazide hydrochloride NCL123 2,2'-bis[(3,4-difluorophenyl)methylene]carbonimidic dihydrazide hydrochloride NCL130 2,2'-bis[(3-bromo-4,5-dimethoxyphenyl)methylene]carbonimidic dihydrazide hydrochloride NCL139 2,2'-bis(3-quinolinylmethylene)carbonimidic dihydrazide hydrochloride NCL146 2,2'-bis(1H-indolylmethylene)carbonimidic dihydrazide hydrochloride NCL147 2,2'-bis(2-quinoxalinylmethylene)carbonimidic azide hydrochloride NCL150 2,2'-bis[3-(4-methoxylphenyl)propenylidene]carbonimidic dihydrazide hydrochloride NCL151 2,2'-bis[(4-hydroxyphenyl)methylene] carbonimidic dihydrazide hydrochloride NCL174 is(4-chlorohydroxyphenylmethylene)carbonimidic dihydrazide hydrochloride NCL175 2,2'-Bis(4-chloropyridinylmethylene) carbonimidic dihydrazide hydrochloride NCL176 2,2'-Bis(2-aminopyridinylmethylene) carbonimidic dihydrazide hydrochloride for the cture of a composition for the ent or prevention of a protozoan colonisation or infection in a subject.
2. The use according to claim 1, wherein the compound is a chloride salt.
3. The use according to claim 1, wherein the composition is adapted to ster the compound to the subject in a dose in the range of 0.1 mg/kg to 250 mg/kg bodyweight.
4. The use according to claim 1, wherein the protozoan colonisation or infection is caused by an organism selected from: Acanthamoeba, Babesia, Balamuthia, Balantidium, tia, Blastocystis, Chilomastix, Cochlosoma, Cryptosporidium, Cyclospora, Cystoisospora, Cytauxzoon, Dientamoeba, Eimeria, Endolimax, Entamoeba, Giardia, Haemoproteus, Hammondia Hartmannella, Hepatozoon, Hexamita, Histomonas, Isospora, ania, Leucocytozoon, Naegleria, Neospora, Pentatrichomonas, Plasmodium, Plasmodium , Sappinia, Sarcocystis, Tetratrichomonas, Theileria, Toxoplasma, Trichomonas, Tritrichomonas, osoma, Tyzzeria and Wenyonella.
5. The use according to claim 1, n the infection or colonisation in the subject is caused by a mixture of at least two protozoan agents.
6. The use according to claim 1, wherein the protozoan ion or colonisation in the subject is a zoonosis.
7. The use ing to claim 1, wherein the protozoan infection or sation in the subject substantially causes an indication selected from: Trypanosomosis; Amboebiasis; Babesiosis; Balantidiosis; Chagas Disease; Cryptosporidiosis; Giardiosis; Leishmaniasis; Malaria; Sarcocystosis; Toxoplasmosis; Cyclosporiasis; Infections caused by free-living Amoebae; Microsporidiosis; Trypanosomiasis; Trichomoniasis; Amoebic dysentery; and Acanthamoebiasis.
8. The use according to claim 1, wherein the therapeutically effective amount of the compound is adapted to be administered to the subject by a route chosen from oral administration, eral administration or topical administration.
9. A method of treating a protozoal colonisation or infection in a non-human animal using a nd chosen from the list comprising: NCL024 2,2'-bis[(4-cyanophenyl)methylene] carbonimidic dihydrazide hydrochloride NCL114 2,2'-bis[(3,5-dichlorophenyl)methylene]carbonimidic dihydrazide hydrochloride NCL123 2,2'-bis[(3,4-difluorophenyl)methylene]carbonimidic dihydrazide hydrochloride NCL130 2,2'-bis[(3-bromo-4,5-dimethoxyphenyl)methylene]carbonimidic dihydrazide hydrochloride NCL139 2,2'-bis(3-quinolinylmethylene)carbonimidic dihydrazide hydrochloride NCL146 2,2'-bis(1H-indolylmethylene)carbonimidic dihydrazide hydrochloride NCL147 2,2'-bis(2-quinoxalinylmethylene)carbonimidic dihydrazide hydrochloride NCL150 is[3-(4-methoxylphenyl)propenylidene]carbonimidic dihydrazide hydrochloride NCL151 2,2'-bis[(4-hydroxyphenyl)methylene] carbonimidic dihydrazide hydrochloride NCL174 2,2'-bis(4-chlorohydroxyphenylmethylene)carbonimidic dihydrazide hydrochloride NCL175 2,2'-Bis(4-chloropyridinylmethylene) carbonimidic dihydrazide hydrochloride NCL176 2,2'-Bis(2-aminopyridinylmethylene) imidic dihydrazide hydrochloride
10. The method according to claim 9, wherein the compound is a chloride salt.
11. The method according to claim 9, wherein the man animal is selected from: canine, , , ovine, e, porcine, avian, e and equine species.
12. A medical device when used in the method of claim 9.
13. The medical device according to claim 12, wherein the medical device is in a form of: a plaster, a e, a dressing or implant applied to a protozoan colonisation or infection in a subject.
14. The method according to claim 9, wherein the compound is administered to the nonhuman animal in a dose in the range of 0.1 mg/kg to 250 mg/kg bodyweight.
15. The method according to claim 9, wherein the protozoan agent colonisation or infection is caused by: Acanthamoeba, Babesia, Balamuthia, Balantidium, Besnoitia, Blastocystis, astix, Cochlosoma, Cryptosporidium, Cyclospora, Cystoisospora, Cytauxzoon, Dientamoeba, Eimeria, Endolimax, Entamoeba, Giardia, Haemoproteus, Hammondia Hartmannella, Hepatozoon, Hexamita, Histomonas, ra, Leishmania, ytozoon, Naegleria, Neospora, Pentatrichomonas, Plasmodium, dium , Sappinia, Sarcocystis, Tetratrichomonas, Theileria, Toxoplasma, Trichomonas, Tritrichomonas, Trypanosoma, Tyzzeria and Wenyonella.
16. The method ing to claim 9, wherein the infection or colonisation in the nonhuman animal is caused by a mixture of at least two protozoan agents.
17. The method ing to claim 9, wherein the protozoan infection or colonisation in the non-human animal is a zoonosis.
18. The method according to claim 9, wherein the protozoan infection or colonisation in the non-human animal substantially causes an tion selected from: Trypanosomosis; Amboebiasis; Babesiosis; Balantidiosis; Chagas e; Cryptosporidiosis; Giardiosis; Leishmaniasis; Malaria; Sarcocystosis; Toxoplasmosis; Cyclosporiasis; Infections caused by free-living Amoebae; Microsporidiosis; Trypanosomiasis; Trichomoniasis; Amoebic dysentery; and Acanthamoebiasis.
19. The method according to claim 9, wherein the eutically effective amount of the compound is administered to the non-human animal by a route chosen from oral administration, parenteral administration or topical administration.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2014903503A AU2014903503A0 (en) | 2014-09-02 | Methods For Treating Protozoan Infections | |
PCT/AU2015/000527 WO2016033635A1 (en) | 2014-09-02 | 2015-08-28 | Methods for treating protozoan infections |
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Publication Number | Publication Date |
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NZ729460A NZ729460A (en) | 2023-08-25 |
NZ729460B2 true NZ729460B2 (en) | 2023-11-28 |
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