Synthesis, antitubercular activity, and molecular modeling studies of analogues of isoliquiritigenin and liquiritigenin, bioactive components from Glycyrrhiza glabra

Isoliquiritigenin (ISL, 1) and liquiritigenin (LTG, 2) were isolated from the rhizomes of Glycyrrhiza glabra. In an attempt to develop potent and selective antituberculosis agents, a series of ISL analogues were synthesized mainly via acid- and base-catalyzed Claisen-Schmidt condensation reaction for their antitubercular activity. Compared to ISL (MIC = 25 mu g/mL), analogues 5, 8, and 10 showed similar antitubercular activity, but, interestingly, 6, 7, and 15 exhibited twofold higher activity (MIC = 12.5 mu g/mL) over ISL, against Mycobacterium tuberculosis. Among the LTG derivatives, LTG 4'-acetate and LTG-oxime were found to be as active (MIC = 25 mu g/mL) as LTG. It is the first report on antimycobacterial activity of these ISL- and LTG-based derivatives. Molecular docking and in silico ADME studies revealed that compounds 6, 7, and 15 are potent inhibitors of M. tuberculosis H(37)Rv alanine dehydrogenase and showed compliance with standard parameters of drug likeness.