Discovery, Synthesis, and Optimization of 1,2,4-Triazolyl Pyridines TargetingMycobacterium tuberculosis

Tuberculosis (TB) results in 1.5 million deaths every year. The rise in multi-drug resistant TB underscores the urgent need to develop new antibacterials, particularly those with new chemical entities and/or novel mechanisms of action that can be used in combination therapy with existing drugs to prevent the rapid emergence of resistance. Herein, we report the discovery and synthesis of a new series of compounds containing a 3-thio-1,2,4-triazole moiety that show inhibition ofMycobacterium tuberculosis(Mtb) growth and survival. Structure-activity relationship studies led us to identify potent analogs displaying nanomolar inhibitor activity, specifically againstMtb. These potent analogs exhibit a promising ADME/pharmacokinetic profile and no cytotoxicity in mammalian cells at over 100 times the effective dose inMtb. Our preliminary investigations into the mechanism of action suggest this series is not engaging promiscuous targets and, thereby, could be acting on a novel target.Abstract Figure