Pharmacophore combination as a useful strategy to discover new antitubercular agents

Article abstract of DOI:10.1007/s00044-013-0645-x

The present study is aimed at combining two well-known pharmacophores (pyrazoline and benzoxazole nucleus) to design and synthesize a series of substituted pyrazoline-based benzoxazole derivatives. In vitro antitubercular evaluation against Mycobacterium tuberculosis H37Rv, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains showed that most of the target compounds displayed potent activity (MIC ~1.25-25 μg/mL) where few compounds were found to be better than isoniazid against MDR-TB (MIC = 3.25 μg/mL) and XDR-TB (MIC = 12.5 μg/mL). Cytotoxicity assay of these active compounds in VERO cell lines displayed good selectivity index. In order to gain insights into the plausible binding motifs, the target compounds were docked into enoyl-acyl carrier protein reductase, a molecular target of isoniazid. All the docked compounds occupied the same hydrophobic binding pocket and interacted mostly by dispersion interactions. Contribution of the three pharmacophoric fragments (pyrazoline, benzoxazole and aryl ring) toward protein-ligand binding was evaluated at semi empirical quantum mechanics level. The interaction energies suggested that most of the binding was governed by the benzoxaxole moiety followed by pyrazoline and aryl rings.