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

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Hexahydroquinoline-3-carbonitrile derivatives; MTT assay; NCI-60 cell lines; cytotoxicity; docking; imatinib; venetoclax.