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
R 1 at each occurrence is independently hydrogen, C 1 -C 10 alkyl, alkenyl, alkynyl, aryl, aryl-C 1 -C 6 alkyl, cycloalkyl, or cycloalkyl-C 1 -C 6 alkyl;
R 2 at each occurrence is independently hydrogen, C 1 -C 10 alkyl, alkenyl, alkynyl, aryl, aryl-C 1 -C 6 alkyl, cycloalkyl, or cycloalkyl-C 1 -C 6 alkyl;
X is O or NH
L 1 is —(CR x R y ) n1 ;
L 2 is —(CR x R y ) n2 ;
L is —(CR x R y ) n3 —(CH 2 CH 2 O) m1 -G-(CH 2 CH 2 O) m2 —(CR x R y ) n4 —
R x and R y at each occurrence is independently hydrogen or C 1 -C 4 alkyl;
G is a bond or -(G 1 ) t -, wherein G 1 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 R 1 , R 2 , R x , R y , and G 1 optionally are each independently substituted with one or more substituents selected from the group consisting of halogen, cyano, —OH, C 1 -C 6 alkoxy, —COOH, C 1 -C 6 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 —(CH 2 ) n3 — and n3 is 4-8.
4. The compound of claim 1 , wherein L is -(G 1 ) t -, and wherein G 1 is aryl and t is 1.
5. The compound of claim 4 , wherein L is
6. The compound of claim 1 , wherein R 1 is C 1 -C 10 alkyl or aryl-C 1 -C 6 alkyl.
7. The compound of claim 1 , where in R 1 is benzyl.
8. The compound of claim 1 , where in R 2 is C 1 -C 10 alkyl, aryl-C 1 -C 6 alkyl, or cycloalkyl-C 1 -C 6 alkyl.
9. The compound of claim 8 , where in R 2 is C 1 -C 6 alkyl.
10. The compound of claim 1 , wherein R 1 is benzyl, R 2 is C 1 -C 6 alkyl, and L is
11. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and an effective amount of a compound of claim 1 .
12. 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 .
13. The method of claim 12 , wherein the infection is a bacterial infection.
14. The method of claim 13 , 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).
15. The method of claim 13 , wherein the bacterial infection is caused by MRSA.
16. The method of claim 13 , wherein the bacterial infection is caused by bacteria that form a bacterial biofilm.
17. The method of claim 16 , wherein the bacterial biofilm is formed by MRSA or E. coli bacteria.
18. The method of claim 13 , wherein the bacterial infection is resistant to treatment with one or more antibiotics.
19. The method of claim 12 , wherein the compound is administered orally, intravenously, transdermally, or topically.
20. The method of claim 19 , wherein the compound is administered topically.