Synthesis, Cytotoxicity Evaluation and Molecular Docking of Fluorine Containing Hexahydroquinoline-3-Carbonitrile Derivatives.

Abstract

Fluorine containing hexahydroquinoline-3-carbonitrile derivatives were found to have potent cytotoxicity. Furthermore, fluorine can modulate pharmacokinetic and pharmacodynamic profile of drugs. Hence, new derivatives containing fluorine were explored as potential cytotoxic agents. Difluoro substituted compounds containing aromatic/heteroaromatic rings were designed, synthesized and screened for in vitro cytotoxicity on cancer cell lines. The active compounds were subjected to docking on Mcl-1 and ADME/T prediction. The synthesized compounds were characterized using various spectral techniques like FT-IR, 1H NMR, 13C NMR and Mass spectra. Compounds were screened for cytotoxicity on NCI-60 cell lines at the National Cancer Institute. The active compounds were evaluated additionally by MTT and SRB assay. Compounds (6l and 6o) showed maximum cytotoxicity with (% GI) of 69 and 63.7 at 10 μM drug concentration, respectively. Compound 6i showed potent cytotoxicity with GI50 of 7.2 μM against Ishikawa cell line. Compound 6o was nearly as active as a reference with IC50 of 9.39 μM and 13.54 μM against HT-29 and HCT-116, respectively, and compound 6l also showed equal potency to that of reference with IC50 of 9.66 μM against Caco-2. Compounds 6i, 6o and 6l showed high docking scores, suggesting their cytotoxicity. Furthermore, ADME/T prediction revealed that all the compounds had drug-likeness properties. Enhanced lipophilic interaction of compounds due to the presence of fluorine in compounds 6i and 6l was revealed during the docking study. Compound 6i can be explored as a lead molecule against other endometrial cancer in futuristic drug development.