Synthesis and SAR Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potential Mycobacterium tuberculosis PafA Inhibitors

Abstract

Tuberculosis (TB) continues to be a significant global health challenge, with the rise of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains increasing the demand for new therapeutic agents with novel mechanisms of action. Proteasome accessory factor A (PafA) is of particular interest due to its role in the virulence of Mycobacterium tuberculosis (Mtb) and its poor sequence conservation in humans. This study focuses on the design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridine analogues as antitubercular agents. Specifically, threeseries of imidazo[1,2-a]pyridine-substituted amino acid hydrazides 44, comprising a total of 120 novel compounds, are synthesised and evaluated for their activity against both drug-resistant and drug-susceptible Mtb strains utilising the Resazurin Microtiter Assay (REMA). A comprehensive structure–activity relationship study is conducted, focusing on the imidazo[1,2-a]pyridine scaffold and its three distinct components: the amino acid moiety (R), the hydrazine component (R1), and the phenyl ring attached to the scaffold (R2). Key SAR findings indicate that an increased amino acid side chain size and the incorporation of small halogens at the meta position of the phenylhydrazine enhance biological activity. To further elucidate these results, the most active compounds are subjected to in silico molecular docking studies to predict their binding interactions with PafA. These findings contribute to ongoing efforts to develop novel and effective antitubercular agents, ultimately advancing therapeutic strategies against TB.