ODCase inhibitors for the treatment of malaria

1. A method of treating or preventing malaria comprising administering to a subject in need thereof a anti-malarial effective amount of a compound selected from a compound of Formula I, tautomers thereof and pharmaceutically acceptable salts, solvates, and prodrugs thereof:

wherein,

R 1 is selected from CN, N 3 , I, Br, NH 2 , NO 2 , C(O)C 1-6 alkyl, NH 1 —C 6 alkyl, N(C 1 -C 6 alkyl) 2 , NHC(O)C 1 -C 6 alkyl and NHC(O)OC 1 -C 6 alkyl;

R 2 is selected from H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, fluoro-substituted-C 1 -C 6 alkyl, fluoro-substituted-C 1 -C 6 alkoxy, N 3 , NH 2 and CN;

R 3 is selected from OH, NH 2 , H and NHC(O)C 1 -C 6 alkyl;

Z is selected from:

wherein,

R 4 is selected from H, C 1 -C 6 alkyl and hydroxy-substituted-C 1 -C 6 alkyl;

One of R 5 and R 6 is hydrogen and the other is selected from H, OH and F and one of R 5′ and R 6′ is hydrogen and the other is selected from H, OH and F or R 5 and R 6 or R 5′ and R 6′ together is ═O or ═CH 2 ;

R 7 is selected from H, F and OH;

R 8 is selected from H, C(O)C 1 -C 6 alkyl, P(O)(OH) 2 , P(O)(OC 1 -C 6 alkyl) 2 and P(O)(OC 1 -C 6 alkyl)OH;

R 9 is selected from H, N 3 , CN, C 1 -C 6 alkyl; and

X—Y is selected from —CH 2 —O—, —O—CH 2 — and —S—CH 2 —.

2. The method according to claim 1 , wherein R 1 in the compounds of Formula I is selected from I, Br, NO 2 , N(C 1 -C 4 alkyl) 2 , NHC(O)C 1 -C 4 alkyl and NHC(O)OC 1 -C 4 alkyl.

3. The method according to claim 2 , wherein R 1 in the compounds of Formula I is selected from I, Br, NO 2 , N(CH 3 ) 2 , NHC(O)CH 3 and NHC(O)CH 3 .

4. The method according to claim 3 , wherein R 1 in the compounds of Formula I is selected from I, Br and N(CH 3 ) 2 .

5. The method according to claim 4 , wherein R 1 in the compounds of Formula I is I.

6. The method according to claim 1 , wherein R 2 in the compounds of Formula I is selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, fluoro-substituted-C 1 -C 4 alkyl, fluoro-substituted-C 1 -C 4 alkoxy, N 3 , NH 2 and CN.

7. The method according to claim 6 , wherein R 2 in the compounds of Formula I is selected from H, fluoro, chloro, bromo, CH 3 , OCH 3 , CF 3 , CF 3 O, N 3 , NH 2 and CN.

8. The method according to claim 7 , wherein R 2 in the compounds of Formula I is selected from H, fluoro, chloro, bromo, OCH 3 and CF 3 , CF 3 O.

9. The method according to claim 1 , wherein R 3 in the compounds of Formula I is selected from OH and NH 2 .

10. The method according to claim 9 , wherein R 3 in the compounds of Formula I is OH and the compound of Formula I has the following tautomeric structure:

11. The method according to claim 1 , wherein in the compounds of Formula I, Z is Formula II.

12. The method according to claim 1 , wherein R 4 in the compounds of Formula I is H.

13. The method according to claim 1 , wherein, R 5 and R 5′ are both OH and R 6 and R 6′ are both H.

14. The method according to claim 1 , wherein R 5 is H, R 5′ is OH and R 6 and R 6′ are both H.

15. The method according to claim 1 , wherein R 7 in the compounds of Formula I is H or OH.

16. The method according to claim 1 , wherein R 8 in the compounds of Formula I is selected from H, C(O)C 1 -C 4 alkyl, P(O)(OH) 2 , P(O)(OC 1 -C 4 alkyl) 2 and P(O)(OC 1 -C 4 alkyl)OH.

17. The method according to claim 16 , wherein R 8 in the compounds of Formula I is selected from H, C(O)CH 3 , P(O)(OH) 2 , P(O)(OCH 3 ) 2 and P(O)(OCH 3 )OH.

18. The method according to claim 17 , wherein R 8 in the compounds of Formula I is selected from H, C(O)CH 3 , and P(O)(OH) 2 .

19. The method according to claim 1 , wherein R 9 in the compounds of Formula I is H.

20. The method according to claim 1 , wherein X—Y is —O—CH 2 —.

21. The method according to claim 1 , wherein the compound of Formula I has the following structure:

22. The method according to claim 1 , wherein the compound of Formula I is selected from the group consisting of:

6-Cyanouridine;

6-Cyanouridine-5′-monophosphate;

6-Azido uridine;

6-Azido uridine-5′-O-monophosphate;

6-Amino uridine-5′-O-monophosphate;

6-Amino uridine;

6-Methyl uridine;

6-Methyl uridine-5′-O-monophosphate;

6-Iodo-uridine;

6-N-Methylamino uridine;

6-N,N-Dimethylamino uracil;

6-N,N-Dimethylamino uridine;

6-N-Methylamino uridine-5′-O-monophosphate;

6-Iodo uridine-5′-O-monophosphate;

5-Fluoro-6-amino uridine;

5-Bromo-6-iodo uridine;

5-Fluoro-6-azido uridine;

5-Fluoro-6-iodo uridine;

5-Fluoro-6-amino uridine-5′-O-monophosphate;

5-Bromo-6-iodo uridine-5′-O-monophosphate;

5-Fluoro-6-azido uridine-5′-O-monophosphate;

5-Fluoro-6-iodo uridine-5′-O-monophosphate;

6-Methoxycarbonyl uridine;

6-Ethoxycarbonyl uridine;

6-Methoxycarbonyl uridine-5′-O-monophosphate;

6-Ethoxycarbonyl uridine-5′-O-monophosphate;

11-Hydroxymethyl-6-iodo-uridine;

11-Hydroxymethyl-6-iodo-uridine-5′-monophosphate, and

pharmaceutically acceptable salts, solvates, and prodrugs thereof.

23. A method of preventing or treating an infection of a malarial parasite in a subject comprising administering to the subject an anti-malarial effective amount of a compound of Formula I, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein the compound of Formula I is as defined in claim 1 .

24. A method of inhibiting ODCase in a plasma or blood sample isolated from a subject comprising adding to said plasma or blood sample an inhibiting effective amount of a compound of Formula I as defined above, and pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein the compound of Formula I is as defined in claim 1 .

25. A compound of Formula I, wherein Formula I is as defined in claim 1 , selected from the group consisting of:

6-(dimethylamino) uridine;

5-fluoro-6-amino uridine;

5-bromo-6-amino uridine;

5-fluoro-6-azido uridine;

1′-Hydroxymethyl-6-iodo-uridine;

6-(dimethylamino) 2′-deoxyuridine;

5-fluoro-6-amino 2′-deoxyuridine;

5-bromo-6-amino 2′-deoxyuridine;

5-fluoro-6-azido 2′-deoxyuridine;

5-chloro-6-iodo 2′-deoxyuridine;

5-chloro-6-azido 2′-deoxyuridine;

5-methoxy-6-iodo 2′-deoxyuridine;

5-methoxy-6-azido 2′-deoxyuridine;

5-methoxy-6-amino 2′-deoxyuridine;

5-bromo-6-iodo 2′-deoxyuridine;

5-bromo-6-azido 2′-deoxyuridine;

6-(dimethylamino) uridine 5′-monophosphate;

5-fluoro-6-amino uridine 5′-monophosphate;

5-bromo-6-amino uridine 5′-monophosphate;

5-fluoro-6-azido uridine 5′-monophosphate;

1′-Hydroxymethyl-6-iodo-uridine-5′-monophosphate

6-(dimethylamino) 2′-deoxyuridine 5′-monophosphate;

5-fluoro-6-amino 2′-deoxyuridine 5′-monophosphate;

5-bromo-6-amino 2′-deoxyuridine 5′-monophosphate;

5-fluoro-6-azido 2′-deoxyuridine 5′-monophosphate;

5-chloro-6-iodo 2′-deoxyuridine 5′-monophosphate;

5-chloro-6-azido 2′-deoxyuridine 5′-monophosphate;

5-methoxy-6-iodo 2′-deoxyuridine 5′-monophosphate;

5-methoxy-6-azido 2′-deoxyuridine 5′-monophosphate;

5-methoxy-6-amino 2′-deoxyuridine 5′-monophosphate;

5-bromo-6-iodo 2′-deoxyuridine 5′-monophosphate;

5-bromo-6-azido 2′-deoxyuridine 5′-monophosphate;

5-fluoro-6-iodo uridine 5′-monophosphate;

6-iodo uridine 5′-acetate;

6-iodo 2′-deoxyuridine 5′-acetate, and

pharmaceutically acceptable salts, solvates, and prodrugs thereof.

26. A pharmaceutical composition comprising one or more of a compound according to claim 25 and a pharmaceutically acceptable carrier therefore.