Send Orders for Reprints to reprints@benthamscience.net Current Drug Discovery Technologies, 2021, 18, 1-11 1 1570-1638/21 $65.00+.00 © 2021 Bentham Science Publishers RESEARCH ARTICLE Synthesis, Cytotoxicity Evaluation and Molecular Docking of Fluorine Containing Hexahydroquinoline-3-Carbonitrile Derivatives Nishith Teraiya 1,* , Subhas S. Karki 2 and Ashlesha Chauhan 1 1 Department of Pharmaceutical Chemistry, K B Institute of Pharmaceutical Education and Research, Kadi Sarva Vish- vavidhyalay, Gandhinagar, Gujarat, 382023, India; 2 Department of Pharmaceutical Chemistry, Dr. Prabhakar B Kore Basic Science Research Center, Off-campus, KLE College of Pharmacy (A constituent unit of KAHER-Belagavi), Raja- jinagar, Bangalore 560010, Karnataka, India ARTICLE HISTORY Received: July 20, 2020 Revised: November 21, 2020 Accepted: November 30, 2020 DOI: 10.2174/1570163817666201229154848 Abstract: Background: Fluorine containing hexahydroquinoline-3-carbonitrile derivatives were found to have potent cytotoxicity. Furthermore, fluorine can modulate pharmacokinetic and phar- macodynamic profile of drugs. Hence, new derivatives containing fluorine were explored as poten- tial cytotoxic agents. Objective: Difluoro substituted compounds containing aromatic/heteroaromatic rings were de- signed, synthesized and screened for in vitro cytotoxicity on cancer cell lines. The active com- pounds were subjected to docking on Mcl-1 and ADME/T prediction. Methods: The synthesized compounds were characterized using various spectral techniques like FT-IR, 1 H NMR, 13 C NMR and Mass spectra. Compounds were screened for cytotoxicity on NCI-60 cell lines at the National Cancer Institute. The active compounds were evaluated additional- ly 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 GI 50 of 7.2 µM against Ishikawa cell line. Compound 6o was nearly as active as a reference with IC 50 of 9.39 µM and 13.54 µM against HT-29 and HCT-116, respectively, and compound 6l also showed equal po- tency to that of reference with IC 50 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 com- pounds 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, cytotoxicity, NCI-60 cell lines, MTT assay, docking, venetoclax, imatinib. 1. INTRODUCTION Cancer has emerged as one of the major leading causes of mortality and death in the world, despite advancement in the treatment with chemotherapy, radiotherapy, selective tar- get inhibitors and various combination therapies based on clinical evidence. The change in living habits and environ- mental pollutions are the stimulating factors that initiate ge- netic mutation and progress in cancer. The WHO has made a statistical prediction about the death of 13.2 million people around the world by 2030. In light of above facts, there is an urgent need for designing small molecules to be potent cyto- toxic agents against cancer [1, 2]. * Address correspondence to this author at the Department of Pharmaceuti- cal Chemistry, K B Institute of Pharmaceutical Education and Research, Se- cor-23, GH-6, Gandhinagar-382023 Gujarat, India; Tel: -91-9429167326; Fax: +91 079 23249069; E-mail: teraiya@gmail.com The hexahydroquinoline-3-carbonitrile derivatives have been reported for anticancer [3-8], antimicrobial [9-12], an- ti-oxidant [13] and anti-tubercular [14, 15] activities. Hex- ahydroquinoline derivatives bearing sulfonamide were re- ported as anticancer agents that act by inhibition of carbonic anhydrase [16-19]. Ghorab MA et al., have reported bromi- nated hexahydroquinoline-3-carbonitrile derivatives as po- tent cytotoxic agents against breast cancer in [Fig. (1a)] [6]. Further, Fluoro, 3, 4-difluoro and 3-trifluoromethyl substitut- ed hexahydroquinoline-3-carbonitrile was reported as a po- tent anticancer agent in [ Fig. ( 1b)] [15-17]. Fluorine is known to alter the pharmacokinetic and pharmacodynamic profile and exhibits good binding affinity. It also shows good lipophilicity, metabolic stability and acts as a hydrogen bond acceptor [20]. These findings inspired us to take active compounds [Fig. 1(a, b)] as lead molecules to modify and explore novel fluorine-containing hexahydroquinoline-3-car- bonitrile to be a potent cytotoxic agent as shown in Fig. (1c).