Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]pyridine-based Mycobacterium tuberculosisglutamine synthetase inhibitors

Abstract

Based on an imidazo[1,2-a]pyridine hit from a high-throughput screening directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a number of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC₅₀ = 3.0 μM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified with single-digit micromolar potency and one with sub-micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize many of the structure–activity relationships observed.