Rifamycin derivatives effective against drug-resistant microbes

1. A rifamycin compound having a structural formula I or II:

wherein,

A is a quinolone or its pharmacophore, covalently coupled to a linker group “X”;

X is a linker group that is covalently coupled to both rifamycin moiety at C-3 position and “A”, wherein “X” is selected from one or a combination of 1 to 3 of the following structural elements:

a) —(C 1 -C 6 )alkylene,

b) —(C 1 -C 6 )alkenylene,

c) —(C 1 -C 6 )alkynylene,

d) —(C 3 -C 8 )cycloalkylene,

e) —O—,

f) —C(H)═N—, provided the group was not directly attached to the C-3 position of the rifamycin moiety,

g) —C(═O)—,

h) —C(═N—O—R 13 )—, wherein R 13 represents hydrogen, (C 1 -C 6 )alkyl, or substituted (C 1 -C 6 )alkyl,

i) —S(O) n —, wherein n is a number between 0 and 2,

j) —N(R 14 )—, wherein R 14 represents hydrogen, (C 1 -C 6 )alkyl, or substituted (C 1 -C 6 )alkyl, and

k) arylene,

wherein, the carbon or nitrogen atoms of the linker group “X” can be substituted by 1 to 3 substituents selected from (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, hydroxyl, and (C 1 -C 6 )alkoxy;

R 1 is hydrogen, or acetyl,

or a pharmaceutically acceptable salt of the structural formula I or II.

2. The rifamycin compound of claim 1 , wherein R 1 is hydrogen.

3. The rifamycin compound of claim 1 , wherein X comprises any one or a combination of the following structures:

4. A rifamycin compound having a structural formula III or IV:

wherein,

R i is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, substituted (C 3 -C 6 )cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R ii is hydrogen, halogen, amino, nitro or methyl group;

Y is C—H, C—F, or N;

Z is C—H, C—F, C—Cl, C—CN, C—CF 3 , C-Me, C—OMe, C—OCH 2 F, C—OCHF 2 , or N;

R 1 is hydrogen, or acetyl;

X is selected from one or a combination of two to three of the following structural elements:

 or a pharmaceutically acceptable salt of the structural formula III or IV.

5. A method of treating a bacterial infection in a subject comprising: administering to the subject an effective amount of the compound of claim 1 or 4 .

6. The method of claim 5 , wherein the microbial infection is caused by a drug resistant bacterium.

7. A compound of the formula: 3-[4-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)piperazin-1-yl]rifamycin S:

8. A compound of the formula: 3-[4-(3-Carboxy-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydronaphthyridin-7-yl)piperazin-1-yl]rifamycin S:

9. A compound of the formula: 3-[4-[3-[1-[3-Carboxy-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydronaphthyridin-7-yl]piperidin-4-yl]propyl]piperidin-1-yl]rifamycin S:

10. A compound of the formula: (R/S)-3-[1-(3-Carboxy-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidin-3-ylamino]rifamycin S:

11. A compound of the formula: (R)-3-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidin-3-ylamino]rifamycin S:

12. A compound of the formula: (S)-3-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidin-3-ylamino]rifamycin S:

13. A compound of the formula: (R,S)-3-[4-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-yl]rifamycin S:

14. An antibiotic, comprising a compound of the formula: (R,S)-3-[4-(3-Carboxy-1-ethyl-6,8-difluoro-4-oxo-1,4-dihydroquinolin-7-yl)-2-methyl-piperazinyl]rifamycin SV:

15. A compound of the formula: 3-[4-[3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-(1,4-dihydroquinolin-7-yl)]-piperazin-1-ylmethyl]rifamycin SV:

16. A compound of the formula: (R/S)-3-[1-(8-Chloro-3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidinyl-3-aminomethyl]rifamycin SV:

17. A compound of the formula: 3-[4-[3-carboxy-1-(2,4-Difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridin-7-yl]piperazin-1-ylmethyl]rifamycin SV:

18. A compound of the formula: (R)-3-[1-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidinyl-3-aminomethyl]rifamycin SV:

19. A compound of the formula: (S)-3-[1-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidinyl-3-aminomethyl]rifamycin SV:

20. A compound of the formula: 3-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)azetidin-3-methylamino)rifamycin S:

21. A compound of the formula: (R/S)-3-[4-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-piperazin-1-yl]rifamycin S:

22. A compound of the formula: (R/S)-3-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidin-3-ylamino-methyl]rifamycin S:

23. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidin-3-ylamino]-piperidin-1-yl}rifamycin S:

24. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidin-3-ylamino]-piperidin-1-yl}rifamycin S:

25. A compound of the formula: 3-{4-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-piperazin-4-yl]-piperidin-1-yl}rifamycin S:

26. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-piperidin-3-ylamino]-piperidin-1-yl}rifamycin S:

27. A compound of the formula: 3-{4-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-azetidin-3-ylamino]-piperidin-1-yl}rifamycin S:

28. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidin-3-ylamino-methyl]-piperidin-1-yl}rifamycin S:

29. A compound of the formula: 3-{4-[6-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-octahydro-pyrrolo[3,4-b]-pyrridin-1-yl]-piperidin-1-yl}rifamycin S:

30. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-(pyrrolidin-3-ylmethyl)-amino]-piperidin-1-yl}rifamycin S:

31. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-1-(2,3-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-7-yl)-(pyrrolidin-3-ylmethyl)-amino]-piperidin-1-yl}rifamycin S:

32. A compound of the formula: 3-{4-[1-(3-Carboxy-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-piperazin-4-yl]-piperidin-1-yl}rifamycin S:

33. A compound of the formula: 3-{4-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidin-3-ylethylamino]-piperidin-1-yl}rifamycin S:

34. A compound of the formula: (R/S)-3-{4-(1-[1-(3-Carboxy-1-(2,3-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-7-yl)-pyrrolidin-3-yl]-piperazin-1-yl)-piperidin-1-yl}-rifamycin S:

35. A compound of the formula: (R/S)-3-[4-{1-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-piperidin-1-yl]-rifamycin S:

36. A compound of the formula: (R/S)-3-{4-({1-[1-(3-Carboxy-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-piperidin-1-yl]-rifamycin S:

37. A compound of the formula: (R/S)-3-{3-[1-(3-Carboxy-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidin-3-ylcarbamoyl]-azetidin-1-yl}rifamycin S:

38. A compound of the formula: (R/S)-3-{3-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidin-3-ylcarbamoyl]-azetidin-1-yl}rifamycin S:

39. A compound of the formula: 3-{3-[4-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-piperazin-1-yl-carbonyl]-azetidin-1-yl}rifamycin S:

40. A compound of the formula: 3-{3-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-piperidin-3-ylcarbamoyl]-azetidin-1-yl}rifamycin S:

41. A compound of the formula: 3-{3-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-azetidin-3-ylcarbamoyl]-azetidin-1-yl}rifamycin S:

42. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidin-3-ylcarbamoyl]-piperidin-1-yl}rifamycin S:

43. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-pyrrolidin-3-ylcarbamoyl]-piperidin-1-yl}rifamycin S:

44. A compound of the formula: 3-{4-[4-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-piperazin-1-ylcarbonyl]-piperidin-1-yl}rifamycin S:

45. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-piperidin-3-ylcarbamoyl]-piperidin-1-yl}rifamycin S:

46. A compound of the formula: 3-{4-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-azetidin-3-ylcarbamoyl]-piperidin-1-yl}rifamycin S:

47. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-1-(2,3-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-7-yl)-pyrrolidin-3-yl]-piperazin-1-yl}-rifamycin S:

48. A compound of the formula: 3-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-7-yl)-piperazin-4-yl]-rifamycin S:

49. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-7-yl)-pyrrolidin-3-yl-cyclopropyl]-piperazin-1-yl}-rifamycin S:

50. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)-pyrrolidin-3-yl-cyclopropyl]-piperazin-1-yl}-rifamycin S:

51. A compound of the formula: (R/S)-3-{4-({1-[1-(3-Carboxy-1-(2,3-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-piperidin-1-yl]-rifamycin S:

52. A compound of the formula: (R/S)-3-{4-[1-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-7-yl)-3-methoxyiminopyrrolidin-4-ylmethylamino]-piperidin-1-yl}rifamycin S:

53. A compound of the formula: 3-[2-[3-Carboxy-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydronaphthyridin-7-yl]-2,7-diaza-spiro[4.5]decyl)-7-yl]rifamycin S: