MymA Bioactivated Thioalkylbenzoxazole Prodrug Family Active against <i>Mycobacterium tuberculosis</i>

Abstract

Screening of a GSK-proprietary library against intracellular <i>Mycobacterium tuberculosis</i> identified <b>1</b>, a thioalkylbenzoxazole hit. Biological profiling and mutant analysis revealed that this compound is a prodrug that is bioactivated by the mycobacterial enzyme MymA. A hit-expansion program including design, synthesis, and profiling of a defined set of analogues with optimized drug-like properties led to the identification of an emerging lead compound, displaying potency against intracellular bacteria in the low micromolar range, high in vitro solubility and permeability, and excellent microsomal stability.