Antibiotic tolerance inhibitors
The present disclosure relates to benzimidazole-benzamide derivatives, and the use thereof, e.g., to treat infections.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y is O;
Ring A is aryl, heteroaryl, or heterocycloalkyl, wherein ring A is unsubstituted or substituted by 1 to 5 R 1 ;
R 1 is —NR a R b , NO 2 , or —NHC(O)R c ; or two R 1 together with the carbon atoms to which they are attached form a heteroaryl or heterocycloalkyl;
R 2 is —NR a R b , —NHC(O)R a , NO 2 , —CN, —SR a , or —S(O) 2 R a ;
R a and R b are each independently H or C 1-6 alkyl;
R c is H, C 1-6 alkyl, or C 1-6 haloalkyl; and
m is 1, 2, 3, or 4.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein Y is O and Ring A is phenyl substituted by 1 to 5 R 1 .
3. A compound which is:
2-((6-nitro-1H-benzo[d]imidazol-2-yl)thio)-N-(4-phenoxyphenyl)acetamide, or a pharmaceutically acceptable salt thereof.
4. A pharmaceutically acceptable composition comprising a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Y is O;
Ring A is aryl, heteroaryl, or heterocycloalkyl, wherein ring A is unsubstituted or substituted by 1 to 5 R 1 ;
R 1 is C 1 -C 6 alkyl, —NR a R b , NO 2 , or —NHC(O)R c ; or two R 1 together with the carbon atoms to which they are attached form a heteroaryl or heterocycloalkyl;
R 2 is —NR a R b , —NHC(O)R a , NO 2 , —CN, —SR a , or —S(O) 2 R a ;
R a and R b are each independently H or C 1-6 alkyl;
R c is H, C 1-6 alkyl, or C 1-6 haloalkyl; and
m is 1, 2, 3, or 4;
and
a pharmaceutically acceptable carrier.
5. The composition of claim 4 , wherein Y is O and Ring A is phenyl substituted by 1 to 5 R 1 .
6. The composition of claim 5 , wherein the compound is
2-((6-nitro-1H-benzo[d]imidazol-2-yl)thio)-N-(4-phenoxyphenyl)acetamide,
or a pharmaceutically acceptable salt thereof.
7. A method of treating an antibiotic-tolerant infection in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition of claim 4 .
8. The method of claim 7 , wherein the compound is 2-((6-nitro-1H-benzo[d]imidazol-2-yl)thio)-N-(4-phenoxyphenyl)acetamide, or a pharmaceutically acceptable salt thereof.
9. The method of claim 7 , wherein the bacterial infection or antibiotic-tolerant infection is caused by a Gram-negative bacterium.
10. The method of claim 9 , wherein the gram-negative bacterium is selected from the group consisting of: Pseudomonas aeruginosa and Burkholderia species.
11. The method of claim 7 , further comprising administering an antibiotic selected from the group consisting of: penicillins, cephalosporins, carbacephems, cephamycins, carbapenems, monobactams, quinolones, tetracyclines, aminoglycosides, macrolides, glycopeptides, chloramphenicols, glycylcyclines, licosamides, lipopeptides, oxazolidinones and fluoroquinolones.
12. The method of claim 7 , wherein the bacterial infection is selected from the group consisting of: pneumonia, septic shock, urinary tract infection, a gastrointestinal infection, and an infection of the skin and soft tissue.
13. The method of claim 7 , wherein the subject is a mammal or plant.
14. A method of treating a Gram negative infection in a subject, the method comprising administering to said subject in need of such treatment a composition of claim 4 .
15. The method of claim 14 , wherein the Gram negative infection is caused by Pseudomonas aeruginosa.
16. The method of claim 14 , wherein the subject is a trauma patient or a burn patient suffering from a burn or skin wound.
17. A method of reducing bacterial tolerance in a subject, the method comprising administering to said subject a composition of claim 4 .
18. The method of claim 14 , further comprising identifying said subject as suffering from a bacteria tolerant infection.
19. The method of claim 14 , further comprising co-administering to said subject an antibiotic.
20. The method of claim 19 , wherein said antibiotic is a quinolone antibiotic.