Design and synthesis of 9H-fluorenone based 1,2,3-triazole analogues as Mycobacterium tuberculosis InhA inhibitors.

We prepared fifty various 9H-fluorenone based 1,2,3-triazole analogues varied with NH, -S-, and -SO2 - groups using click chemistry. The target compounds were characterized by routine analytical techniques, 1 H, 13 CNMR, mass, elemental, single-crystal XRD (8a) and screened for in vitro antitubercular activity against Mycobacterium tuberculosis (MTB) H37Rv strain and two "wild" strains Spec. 210 and Spec. 192 and MIC50 was determined. Further, the compounds were evaluated for MTB InhA inhibition study as well. The final analogues exhibited minimum inhibitory concentration (MIC) ranging from 52.35 to >295 µm. Among the -NH- analogues, one compound 5p (MIC 58.34 µm), among -S- containing analogues four compounds 8e (MIC 66.94 µm), 8f (MIC 74.20 µm), 8g (MIC 57.55 µm), and 8q (MIC 56.11 µm), among -SO2 - containing compounds one compound 10p (MIC 52.35 µm) showed less than MTB MIC 74.20 µm: Compound 4-(((9H-fluoren-9-yl)sulfonyl)methyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole (10p) was found to be the most active compound with 73% InhA inhibition at 50 µm; it inhibited MTB with MIC 52.35 µm. Further, 10f and 10p were docked to crystal structure of InhA to know binding interaction pattern. Most active compounds were found to be non-cytotoxic against HEK 293 cell lines at 50 µm.

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.

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 >200µM. Among the tested compounds, 7i, 7y and 7z exhibited moderate activity (MIC=24.03-29.19µM) and 7j exhibited very good anti-tubercular activity (MIC=6.16µM). 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.