Design and 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 -SO - groups using click chemistry. The target compounds were characterized by routine analytical techniques, H, 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 MIC 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 -SO - 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.

Anti-Tubercular Properties of 4-Amino-5-(4-Fluoro-3- Phenoxyphenyl)-4H-1,2,4-Triazole-3-Thiol and Its Schiff Bases: Computational Input and Molecular Dynamics

“…Computational studies revealed strong binding with enoyl-acyl carrier protein reductase [53]. Heterocyclic hybrids of triazole inhibited MTB after binding with enoyl reductase (inhA) [54]. A virtual screening study against Mycobacterium N-acetylglucosamine -1-phosphate uridyltransferase discovered several compounds with a triazole nucleus and produced 20-60% inhibition of the enzymatic activity [55].…”

Intermolecular Three-Component Synthesis of Fluorene Derivatives by a Rhodium-Catalyzed Stitching Reaction/Remote Nucleophilic Substitution Sequence

“…In addition, anionic forms of fluorene derivatives are often employed as effective ligands to transition metals, and some of these metal complexes can be used as catalysts for organic transformations including olefin polymerization . Furthermore, some fluorenes having a heteroatom substituent at their bridging carbon (9-position) are known to exhibit biological activity . Because of the high utility of this structural motif, various synthetic methods of fluorenes and their derivatives have been developed to date, but most of the existing methods rely on the use of intramolecular processes as exemplified in the classical Friedel–Crafts cyclization, radical cyclization, and more recent transition-metal-catalyzed cyclization involving C–H bond activation .…”