Antibacterial picolinamide compounds
Here we report the discovery of 2-(4-(3-(trifluoromethoxy)phenoxy)picolinamido)benzo[d]oxazole-5-carboxylate as an antibacterial with potent and selective activity against C. difficile . Its MIC 50 and MIC 90 values, documented across 101 strains of C. difficile , are 0.12 and 0.25 μg/mL, respectively. The compound is effective against C. difficile both at the logarithmic (vegetative) and stationary phases of growth. It targets cell-wall biosynthesis, as assessed both by macromolecular biosynthesis assays and by scanning-electron microscopy. Animals infected with a lethal dose of C. difficile and treated with compound 1 had better survival compared to treatment with vancomycin, which is the front-line antibiotic used for severe recurrent C. difficile infection.
1 . A compound of Formula I:
or a salt thereof,
wherein
Het is
Q 1 is O, absent, S, or NR w ;
Q 2 is CH or N;
each R w is independently H, —(C 1 -C 6 ) alkyl, or a protecting group;
R x , R y , and R z are each independently H, halo, OH, CN, CO 2 H, NO 2 , —(C 1 -C 6 ) alkyl, —CO 2 (C 1 -C 6 ) alkyl, —O(C 1 -C 6 ) alkyl, or —OC(═O) (C 1 -C 6 ) alkyl;
R 1 is OR a , SR a , halo, CN, NO 2 , —(C 1 -C 6 ) alkyl, NR w , or heterocyclyl,
wherein each R a is independently CF 3 , —(C 1 -C 6 ) alkyl, —C(═O) (C 1 -C 6 ) alkyl, or H;
R 2 is OH, —O(C 1 -C 6 ) alkyl, —O(C 3 -C 6 ) cycloalkyl, or —CCH;
R 3 is H, —(C 1 -C 6 ) alkyl or —(C 3 -C 6 ) cycloalkyl; and
Y 1 , Y 2 , Y 3 , and Y 4 are each independently CH or N wherein at least one of Y 1 to Y 4 is N;
wherein each (C 1 -C 6 ) alkyl moiety is independently saturated or unsaturated and optionally substituted.
2 . The compound of claim 1 wherein Q 2 is CH.
3 . The compound of claim 1 wherein R x , R y , and R z are H.
4 . The compound of claim 1 wherein Y 1 is N, and Y 2 , Y 3 , and Y 4 are CH.
5 . The compound of claim 1 wherein R 1 is OR a .
6 . The compound of claim 1 wherein the compound is represented by Formula II:
or a salt thereof.
7 . The compound of claim 6 wherein Q 1 is O.
8 . The compound of claim 6 wherein R a is CF 3 .
9 . The compound of claim 6 wherein R 2 is OH.
10 . The compound of claim 6 wherein the compound is 2-(4-(3-(trifluoromethoxy) phenoxy) picolinamido)benzo[d]oxazole-5-carboxylic acid (1):
or a salt thereof.
11 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent, carrier, or excipient.
12 . The composition of claim 11 wherein the compound is 2-(4-(3-(trifluoromethoxy) phenoxy) picolinamido)benzo[d]oxazole-5-carboxylic acid (1).
13 . A method for treating a bacterial infection comprising administering to a subject in need thereof an effective antibacterial amount of a compound of claim 1 wherein the bacterial infection is thereby treated.
14 . The method of claim 13 wherein the bacterial infection is a Clostridioides difficile ( C. difficile ) infection.
15 . The method of claim 14 wherein the compound selectively inhibits the growth or proliferation of C. difficile.
16 . The method of claim 15 wherein a minimum concentration to inhibit the growth or proliferation of 50% of C. difficile (MIC 50 ) is about 1 μg/mL or less.
17 . The method of claim 15 wherein an effective antibacterial amount of the compound administered as a single dose is about 50 mg/kg or less.
18 . The method of claim 13 wherein the compound is 2-(4-(3-(trifluoromethoxy) phenoxy) picolinamido)benzo[d]oxazole-5-carboxylic acid (1).
19 . The method of claim 13 wherein the compound inhibits peptidoglycan biosynthesis.