Discovery of potent antitubercular agents: Design, synthesis and biological evaluation of 4-(3-(4-substitutedpiperazin-1-yl)-quinoxalin-2-yl)-naphthalen-1-ol analogues.

A series of twenty-five novel 4-(3-(4-substituted piperazin-1-yl)-quinoxalin-2-yl)-naphthalen-1-ol analogues were synthesized, characterized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain. These compounds exhibited minimum inhibitory concentration in the range of 1.56-50 µg/mL. Among these derivatives, compounds 5a, 5b, 5f, 5m, 5p, and 5r displayed moderate activity (MIC 6.25 µg/mL). Compounds 5c, 5d, 5g, 5l, and 5o showed significant antitubercular activity (MIC 3.125 µg/mL), while compounds 5h, 5n, and 5q exhibited potent antitubercular activity (MIC 1.56 µg/mL). In addition, MTT assay was performed on the active analogues of the series against mouse macrophage cells to assess the cytotoxic effect of the newly synthesized compounds, and a selectivity index of the compounds was established. Selectivity index values of the most active compounds (5h, 5n, and 5q) are >47, indicating the compounds' suitability for further potential drug development. A molecular docking study was performed to understand the putative binding mode and binding strength of the selected significantly active and weakly active compounds with the target enzyme mycobacterial topoisomerase II using moxifloxacin as standard. In-silico ADME prediction and bioavailability studies of the titled compounds obey Lipinski's rule of five and Jorgensen's rule of three. To further ascertain the structure of the compounds, a suitable single crystal for the compounds 5a, 6, and 7d was developed and studied.

Synthesis and evaluation of anti-tubercular activity of 6-(4-substitutedpiperazin-1-yl) phenanthridine analogues.

A series of seventeen new 6-(4-substitutedpiperazin-1-yl)phenanthridine derivatives were designed, synthesized, and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Rv by Microplate Alamar Blue Assay and most active compounds were tested for cytotoxicity studies against mouse macrophage cell lines (RAW264.7). Among the tested compounds, ten compounds exhibited significant activity against the growth of M. tuberculosis (MIC ranging from 1.56 to 6.25 µg/mL). In particular, compounds 5e, 5j and 5k displayed excellent activity against the growth of M. tuberculosis (MIC 1.56 µg/mL). The selectivity index values were found to be >25, indicating compounds likeliness in drug development for tuberculosis. The structure of 5k is substantiated by X-ray crystallographic study. Structure-activity correlation indicates the importance of substituent at 4th position of piperazinyl phenanthridine ring.