Design, synthesis and anti-mycobacterial evaluation of imidazo[1,2-<i>a</i>]pyridine analogues.
Khetmalis YM, Chitti S, Umarani Wunnava A, Karan Kumar B, Murali Krishna Kumar M, Murugesan S, Chandra Sekhar KVG.
Based on the molecular hybridization strategy, thirty-four imidazo[1,2-<i>a</i>]pyridine amides (IPAs) and imidazo[1,2-<i>a</i>]pyridine sulfonamides (IPSs) were designed and synthesized. The structures of the target compounds were characterized using <sup>1</sup>H NMR, <sup>13</sup>C NMR, LCMS, and elemental analyses. The synthesized compounds were evaluated <i>in vitro</i> for anti-tubercular activity using the microplate Alamar Blue assay against <i>Mycobacterium tuberculosis</i> H37Rv strain and the MIC was determined. The evaluated compounds exhibited MIC in the range 0.05-≤100 μg mL<sup>-1</sup>. Among these derivatives, <b>IPA-</b>6 (MIC 0.05 μg mL<sup>-1</sup>), <b>IPA-</b>9 (MIC 0.4 μg mL<sup>-1</sup>), and <b>IPS-</b>1 (MIC 0.4 μg mL<sup>-1</sup>) displayed excellent anti-TB activity, whereas compounds <b>IPA-</b>5, <b>IPA-</b>7 and <b>IPS-</b>16 showed good anti-TB activity (MIC 0.8-3.12 μg mL<sup>-1</sup>). The most active compounds with MIC of <3.125 μg mL<sup>-1</sup> 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 <i>in silico</i>. Further, using the Glide module of Schrodinger software, a molecular docking study of <b>IPA-</b>6 was carried out to estimate the binding pattern at the active site of enoyl acyl carrier protein reductase from <i>Mycobacterium tuberculosis</i> (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 <b>IPA-</b>6 on the selected target protein. <b>IPA-</b>6, the most active compound, was found to be 125 times more potent than the standard drug ethambutol (MIC 6.25 μg mL<sup>-1</sup>).