<i>In vitro</i> anti-TB properties, <i>in silico</i> target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against <i>Mycobacterium tuberculosis</i>

Abstract

The alarming increase in multi- and extensively drug-resistant (MDR and XDR) strains of <i>Mycobacterium tuberculosis</i> (MTB) has triggered the scientific community to search for novel, effective, and safer therapeutics. To this end, a series of 3,5-disubstituted-1,2,4-oxadiazole derivatives (<b>3a-3i</b>) were tested against H37Rv, MDR and XDR strains of MTB. Of which, compound <b>3a</b> with para-trifluorophenyl substituted oxadiazole showed excellent activity against the susceptible H37Rv and MDR-MTB strain with a MIC values of 8 and 16 µg/ml, respectively.To understand the mechanism of action of these compounds (<b>3a-3i</b>) and identify their putative drug target, molecular docking and dynamics studies were employed against a panel of 20 mycobacterial enzymes reported to be essential for mycobacterial growth and survival. These computational studies revealed polyketide synthase (Pks13) enzyme as the putative target. Moreover, <i>in silico</i> ADMET predictions showed satisfactory properties for these compounds, collectively, making them, particularly compound <b>3a</b>, promising leads worthy of further optimisation.