Design, synthesis and anti-mycobacterial evaluation of imidazo[1,2-a]pyridine analogues

Abstract

Based on the molecular hybridization strategy, thirty-four imidazo[1,2-a]pyridine amides (IPAs) and imidazo[1,2-a]pyridine sulfonamides (IPSs) were designed and synthesized. The structures of the target compounds were characterized using ¹H NMR, ¹³C NMR, LCMS, and elemental analyses. The synthesized compounds were evaluated in vitro for anti-tubercular activity using the microplate Alamar Blue assay against Mycobacterium tuberculosis H37Rv strain and the MIC was determined. The evaluated compounds exhibited MIC in the range 0.05–≤100 μg mL⁻¹. Among these derivatives, IPA-6 (MIC 0.05 μg mL⁻¹), IPA-9 (MIC 0.4 μg mL⁻¹), and IPS-1 (MIC 0.4 μg mL⁻¹) displayed excellent anti-TB activity, whereas compounds IPA-5, IPA-7 and IPS-16 showed good anti-TB activity (MIC 0.8–3.12 μg mL⁻¹). The most active compounds with MIC of <3.125 μg mL⁻¹ were screened against human embryonic kidney cells to check their cytotoxicity to normal cells. It was observed that these compounds were nontoxic (SI value ≥66). The ADMET characteristics of the final compounds were also predicted in silico. Further, using the Glide module of Schrodinger software, a molecular docking study of IPA-6 was carried out to estimate the binding pattern at the active site of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis (PDB 4TZK). Finally, molecular dynamics simulations were performed for 100 ns to elucidate the stability, conformation, and intermolecular interactions of the co-crystal ligand and significantly active compound IPA-6 on the selected target protein. IPA-6, the most active compound, was found to be 125 times more potent than the standard drug ethambutol (MIC 6.25 μg mL⁻¹).