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

Abstract

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 of Mycobacterium tuberculosis (Mtb) growth and survival. Structure-activity relationship studies led us to identify potent analogs displaying nanomolar inhibitor activity, specifically against Mtb. These potent analogs exhibit a promising ADME/pharmacokinetic profile and no cytotoxicity in mammalian cells at over 100 times the effective dose in Mtb. 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/516356v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1fd7a78org.highwire.dtl.DTLVardef@738c7dorg.highwire.dtl.DTLVardef@c7957org.highwire.dtl.DTLVardef@f26ae3_HPS_FORMAT_FIGEXP M_FIG C_FIG