Design, synthesis of 9H-fluorenone based 1,2,3-triazole analogues as Mycobacterium tuberculosis 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, ¹H, ¹³CNMR, 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 - > 295 μM. Among the -NH- analogues one compound 5p (MIC 58.34 μM), amongst -S- containing analogues four compounds 8e (MIC 66.94 μM), 8f (MIC 74.20 μM), 8g (MIC 57.55 μM) & 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 & 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.

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Fifty novel compounds are synthesized and evaluated for their MTB activity and MTB InhA inhibition study. in vitro cytotoxicity studies of the most active compounds was analysed.10p emerged as most active compound inhibition 73% at 50 µM against MTB InhA and inhibited MTB with MIC 52.35 µM.

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