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.

A 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 as PowerPoint slide