Design and synthesis of 9<i>H</i>‐fluorenone based 1,2,3‐triazole analogues as <i>Mycobacterium tuberculosis</i> InhA inhibitors

Abstract

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.