Time-dependent diaryl ether inhibitors of InhA: structure-activity relationship studies of enzyme inhibition, antibacterial activity, and in vivo efficacy.

ABSTRACT: The diaryl ethers are a novel class of antituberculosis drug candidates that inhibit InhA, the enoyl-ACP reductase involved in the fatty acid biosynthesis (FASII) pathway, and have antibacterial activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. In the present work, we demonstrate that two time-dependent B-ring modified diaryl ether InhA inhibitors have antibacterial activity in a mouse model of TB infection when delivered by intraperitoneal injection. We propose that the efficacy of these compounds is related to their residence time on the enzyme, and to identify structural features that modulate drug-target residence time in this system, we have explored the inhibition of InhA by a series of B-ring modified analogues. Seven ortho-substituted co

SUBMITTER: Pan P 

PROVIDER: S-EPMC4126670 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature