Bis-cyclic guanidines as antibacterial agents
Provided are novel bis-cyclic guanidine compounds, and the use thereof for treating bacterial infection.
1. A compound of formula (I), or a salt thereof
wherein
R1 at each occurrence is independently hydrogen, C1-C10 alkyl, aryl, aryl-C1-C6 alkyl, cycloalkyl, or cycloalkyl-C1-C6 alkyl;
R2 at each occurrence is independently hydrogen, C1-C10 alkyl, aryl, aryl-C1-C6 alkyl, cycloalkyl, or cycloalkyl-C1-C6 alkyl;
X is NH
L1 is —(CRxRy)n1;
L2 is —(CRxRy)n2;
L is —(CRxRy)n3-(CH2CH2O)m1-G-(CH2CH2O)m2-(CRxRy)n4-
Rx and Ry at each occurrence is independently hydrogen or C1-C4 alkyl;
G is a bond or -(G1)t-, wherein G1 at each occurrence is independently aryl, cycloakyl, heteroaryl, or heterocycle;
n1 and n2 are each independently 1-4;
m1, m2, n3, and n4 are each independently 0-10;
t is 1, 2, 3, or 4; and
wherein R1, R2, Rx, Ry, and G1 optionally are each independently substituted with one or more substituents selected from the group consisting of halogen, cyano, —OH, C1-C6 alkoxy, —COOH, C1-C6 alkoxycarbonyl, oxo, and amino.
2. The compound of claim 1 , having a structure of formula (I-a)
3. The compound of claim 1 , wherein L is —(CH2)n3- and n3 is 4-8.
4. The compound of claim 1 , wherein L is -(G1)t-, and wherein G1 is aryl and t is 1.
5. The compound of claim 4 , wherein L is
6. The compound of claim 1 , wherein R1 is C1-C10 alkyl or aryl-C1-C6 alkyl.
7. The compound of claim 1 , where in R1 is benzyl.
8. The compound of claim 1 , where in R2 is C1-C10 alkyl, aryl-C1-C6 alkyl, or cycloalkyl-C1-C6 alkyl.
9. The compound of claim 1 , wherein R1 is benzyl, R2 is C1-C6 alkyl, and L is
10. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and an effective amount of a compound of claim 1 .
11. A method of treating infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 .
12. The method of claim 11 , wherein the infection is a bacterial infection.
13. The method of claim 12 , wherein the bacterial infection is caused by a bacteria selected from the group consisting of K. pneumoniae, P. aeruginosa, E. coli , vancomycin-resistant Enterococcus faecalis , Methicillin-resistant S. aureus (MRSA), and Methicillin-resistant S. epidermidis (MRSE).
14. The method of claim 12 , wherein the bacterial infection is caused by MRSA.
15. The method of claim 12 , wherein the bacterial infection is caused by bacteria that form a bacterial biofilm.
16. The method of claim 15 , wherein the bacterial biofilm is formed by MRSA or E. coli bacteria.
17. The method of claim 12 , wherein the bacterial infection is resistant to treatment with one or more antibiotics.
18. The method of claim 11 , wherein the compound is administered orally, intravenously, transdermally, or topically.
19. The method of claim 18 , wherein the compound is administered topically.
20. A compound selected from the group consisting of the compounds disclosed in the Table below:
and pharmaceutically acceptable salts thereof.