2-aminoimidazole-phenyl derivatives useful for controlling microbial growth

1. A compound of Formula (I):

wherein:

R 1 is selected from the group consisting of H and lower alkyl;

R 2 is selected from the group consisting of H, lower alkyl, aryl, and heteroaryl;

R 3 is selected from the group consisting of H, halo and alkoxy;

or R 2 and R 3 together form a fused ring; and

R 4 and R 5 are each independently selected from the group consisting of H, alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl,

or a pharmaceutically acceptable salt or prodrug thereof.

2. The compound of claim 1 , wherein said compound is a compound of Formula (I)(a):

wherein:

R 1 , R 2 and R 3 are as defined above, and

D 1 , D 2 , D 3 , D 4 , and D 5 are each independently selected from the group consisting of H, halo, alkyl, acyl, alkoxy, aryl, heteroaryl, amino, amide, nitro, hydroxyl, thiol, sulfone, sulfoxide, nitrile, nitro, and haloalkyl,

or wherein D 1 and D 2 , D 2 and D 3 , D 3 and D 4 , or D 4 and D 5 together form a fused ring, optionally substituted,

or a pharmaceutically acceptable salt or prodrug thereof.

3. The compound of claim 2 , wherein at least one of D 1 , D 2 , D 3 , D 4 , and D 5 is lower alkyl,

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , wherein D 3 is lower alkyl,

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , wherein D 3 is n-propyl or n-butyl,

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , wherein said compound is a compound of Formula (I)(a)(1):

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 2 , wherein at least one of D 1 , D 2 , D 3 , D 4 , and D 5 is heteroaryl,

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2 , wherein D 2 is heteroaryl,

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein D 2 is 2-amino imidazole,

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 , wherein said compound is a compound of Formula (I)(a)(2):

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 2 , wherein at least one of D 1 , D 2 , D 3 , D 4 , and D 5 is halo,

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 2 , wherein D 2 and D 4 are each halo,

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12 , wherein D 2 and D 4 are each Br,

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 , wherein said compound is a compound of Formula (I)(a)(3):

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 2 , wherein:

at least one of D 1 , D 2 , D 3 , D 4 , and D 5 is halo; and

at least one of D 1 , D 2 , D 3 , D 4 , and D 5 is haloalkyl,

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15 , wherein D 3 is fluoro-alkyl, and D 4 is halo,

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 16 , wherein D 3 is trifluoromethyl, and D 4 is Cl,

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 , wherein R 2 is lower alkyl,

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18 , wherein said compound is a compound of Formula (I)(a)(4):

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 , wherein said compound is a compound of Formula (I)(b):

wherein:

R 1 , R 2 and R 3 are as defined above, and

D 6 , D 7 , D 8 , D 9 , and D 10 are each independently selected from the group consisting of H, halo, alkyl, acyl, alkoxy, aryl, heteroaryl, amino, amide, nitro, hydroxyl, thiol, sulfone, sulfoxide, nitrile, nitro, and haloalkyl,

or wherein D 6 and D 7 , D 7 and D 8 , D 8 and D 9 , or D 9 and D 10 together form a fused ring,

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20 , wherein at least one of D 6 , D 7 , D 8 , D 9 , and D 10 is heteroaryl,

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21 , wherein D 8 is heteroaryl,

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 22 , wherein D 8 is 2-amino imidazole,

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 23 , wherein said compound is a compound of Formula (I)(b)(1):

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 20 , wherein D 8 and D 9 together form a fused ring, optionally substituted,

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 25 , wherein D 8 and D 9 form a cyclohexane or cyclohexene fused ring, optionally substituted,

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 26 , wherein said compound is a compound of Formula (I)(b)(2):

or a pharmaceutically acceptable salt thereof.

28. The compound of claim 27 , said compound is a compound of Formula (I)(b)(3):

or a pharmaceutically acceptable salt thereof.

29. A composition comprising a carrier and an effective amount of the compound of claim 1 .

30. The composition of claim 29 , wherein said composition is formulated for topical use.

31. The composition of claim 29 , wherein said composition is an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.

32. A composition comprising the compound of claim 1 covalently coupled to a substrate.

33. A coating composition, comprising:

(a) a film-forming resin;

(b) a solvent that disperses said resin;

(c) an effective amount of the compound of claim 1 , wherein said effective amount of said compound enhances the effects of an antibiotic that is administered in combination with the compound; and

(d) optionally, at least one pigment.

34. The coating composition of claim 33 , wherein said compound is covalently coupled to said resin.

35. The coating composition of claim 33 , wherein said resin comprises a polymeric material.

36. A substrate coated with the coating composition of claim 33 .

37. A method of reducing microbial growth on a substrate comprising the step of contacting the compound of claim 1 to said substrate in an amount effective to enhance the effects of an antibiotic that is administered in combination with the compound.

38. The method of claim 37 , wherein said microbial growth is Gram-negative bacterial growth.

39. The method of claim 38 , wherein said bacterial growth is Acinetobacter baumannii, Klebsiella pneumoniae , or Escherichia coli.

40. The method of claim 38 , wherein said bacterial growth is carbapenem resistant strains of Acinetobacter baumannii, Klebsiella pneumoniae , or Escherichia coli.

41. A method for treating a bacterial infection in a subject in need thereof, comprising administering to said subject the compound of claim 1 in an amount effective to enhance the effects of an antibiotic that is administered in combination with the compound.

42. The method of claim 41 , wherein said bacterial infection comprises Gram-negative bacteria.

43. The method of claim 41 , wherein said bacterial infection comprises Acinetobacter baumannii, Klebsiella pneumoniae , or Escherichia coli.

44. The method of claim 41 , wherein said bacterial infection comprises carbapenem resistant strains of Acinetobacter baumannii, Klebsiella pneumoniae , or Escherichia coli.

45. The method of claim 41 , wherein a biocide is administered to said subject in combination with the compound.

46. The method of claim 45 , wherein the compound is administered to said subject in an amount effective to enhance the effects of the biocide.

47. A medical device comprising:

(a) a medical device substrate; and

(b) an effective amount of the compound of claim 1 , either coating the substrate, or incorporated into the substrate, wherein said effective amount of said compound enhance the effects of an antibiotic that is administered in combination with the compound.

48. The medical device of claim 47 , wherein said medical device substrate is selected from the group consisting of stents, fasteners, ports, catheters, scaffolds and grafts.

49. The medical device of claim 47 , wherein said compound is covalently coupled to said substrate.