Discovery of new antitubercular agents by combining pyrazoline and benzoxazole pharmacophores: design, synthesis and insights into the binding interactions

Abstract

The present study is aimed at combining two well-known pharmacophores (pyrazoline and benzoxazole nucleus) to design and synthesize a series of new benzoxazole-based pyrazoline derivatives. In vitro antitubercular evaluation against Mycobacterium tuberculosis H₃₇Rv and multidrug-resistant TB (MDR-TB) strains showed that most of the target compounds displayed potent activity (MIC ~0.625–25 μg/mL). Few compounds were found to be better than isoniazid against MDR-TB (MIC = 3.25 μg/mL). In order to gain insights into the plausible binding motifs, the target compounds were docked into enoyl-acyl carrier protein (ACP) reductase, a molecular target of isoniazid. Many compounds were successfully docked into the active site of enoyl-ACP reductase and all the docked compounds occupied the same hydrophobic binding pocket and interacted mostly by dispersion interactions with the neighboring residues Met103, Met155, Tyr158, Met199, Ile202, Ile215, and Leu218. Contribution of the three pharmacophoric fragments (pyrazoline, benzoxazole and aryl ring) towards protein–ligand binding was evaluated at semi-empirical quantum mechanics level. The interaction energies suggested that most of the binding was governed by the benzoxazole moiety followed by pyrazoline and aryl rings.