Seeking potent anti-tubercular agents: Design, synthesis, anti-tubercular activity and docking study of various ((triazoles/indole)-piperazin-1-yl/1,4-diazepan-1-yl)benzo[d]isoxazole derivatives

•38 novel benzo[d]isoxazoles were synthesised and evaluated for anti-TB activity.•4 analogues (MIC < 30 μM) exhibited very good anti-TB activity against 3 MTB strains.•In vitro cytotoxicity studies of the most active compounds were analysed.•All compounds docking scores displayed in between −7.1 and −10.7 kcal/mol.•Compound 7j was docking with mycobacterial PS enzyme (4MQ6.pdb).

A series of thirty eight novel 3-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl/1,4-diazepan-1-yl)benzo[d]isoxazole and 1-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl/1,4-diazepan-1-yl)-2-(1H-indol-3-yl)substituted-1-one analogues were synthesised, characterised using various analytical techniques and evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain and two ‘wild’ strains Spec. 210 and Spec. 192. The titled compounds exhibited minimum inhibitory concentration (MIC) ranging from 6.16 to >200 μM. Among the tested compounds, 7i, 7y and 7z exhibited moderate activity (MIC = 24.03–29.19 μM) and 7j exhibited very good anti-tubercular activity (MIC = 6.16 μM). Furthermore, 7i, 7j, 7y and 7z were found to be non-toxic against mouse macrophage cell lines when screened for toxicity. All the synthesised compounds were docked to pantothenate synthetase enzyme site to know deferent binding interactions with the receptor.

Graphical abstractA series of thirty eight novel compounds are synthesised and evaluated for their anti-TB activity. Amongst them, compound 7j exhibited very good anti-TB activity with MIC 6.16 μM and SI was >36. In addition, docking studies for all compounds were performed on mycobacterial pantothenate synthase enzyme and interaction pattern of the compound 7j was analysed.Figure optionsDownload full-size imageDownload as PowerPoint slide