Compounds and methods for treatment of bacterial infections
This document discloses a novel class of compounds for inhibiting bacterial growth and treating bacterial infection. The compounds target a key step of the futalosine pathway and therefore are effective for the selective inhibition of certain bacterial species and genera with reduced side effect in comparison with conventional antibiotics.
1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula I,
wherein:
R 1 in each instance independently is hydrogen or C 1-10 alkyl, wherein the C 1-10 alkyl is optionally substituted with one or more selected from the group consisting of a halogen, oxo (═O), OH, OC 1-4 alkyl, SC 1-4 alkyl, and arylC 1-6 alkyl;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, CN, C 1-6 alkylCONH, C 1-6 alkylNHCO, C 1-6 alkylSO 2 NH, C 1-6 alkylNHSO 2 , and C 1-6 alkylSO 2 ;
X is O, S, NH or CH 2 ;
and
Z in each instance independently is C or N, provided that:
when a Z is N, the substituent R 2 , R 3 , R 4 , or R 5 attached thereto is void; and
when each Z is C, at least one of R 2 , R 3 , R 4 , and R 5 is chlorine or fluorine.
2. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is represented by Formula I-c,
wherein
R 1 is hydrogen or C 1-6 alkyl;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, and C 1-6 alkyl.
3. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is hydrogen.
4. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein at least one of R 2 , R 3 , R 4 , and R 5 is fluorine.
5. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein R 2 , R 3 , R 4 , and R 5 are each independently hydrogen or fluorine.
6. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is selected from the group consisting of
7. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 1 .
8. The pharmaceutical composition of claim 7 , wherein the compound is selected from the group consisting of
9. A method of treating a bacterial infection or inhibiting the proliferation of bacteria in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 1 .
10. The method of claim 9 , wherein the compound or the pharmaceutically acceptable salt thereof is selective for the bacteria over Clostridium difficile, Escherichia coli or any other species that lacks the futalosine pathway.
11. The method of claim 9 , wherein the bacteria belongs to a genus selected from the group consisting of Helicobacter, Campylobacter, Streptococcus, Clostridium, Mycoplasma, Lactobacillus, Staphylococcus, Bifidobacterium, Rickettsia , and Brucella.
12. The method of claim 9 , wherein the bacteria belongs to Helicobacter genus.
13. The method of claim 9 , wherein the bacteria is Helicobacter pylori.
14. The method of claim 9 , wherein the subject is a human.
15. The method of claim 9 , wherein the compound is selected from the group consisting of
16. The method of claim 9 wherein the bacteria is Helicobacter pylori and the compound is
17. A method of inhibiting MqnE in a bacterial cell, comprising contacting the cell with an effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 1 .
18. The method of claim 17 , wherein the bacterial cell belongs to a genus selected from the group consisting of Helicobacter, Campylobacter, Streptococcus, Clostridium, Mycoplasma, Lactobacillus, Staphylococcus, Bifidobacterium, Rickettsia , and Brucella.
19. The method of claim 17 , wherein the bacterial cell is Helicobacter pylori.
20. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is