title: Novel aminoalkylated azaphenothiazines as potential inhibitors of T98G, H460 and SNU80 cancer cell lines in vitro.
abstract: A set of twenty-one novel aminoalkylated azaphenothiazines is synthesized using a two-step methodology starting from azaphenothiazines. The key step was the selective monoalkylation at position 10 of azaphenothiazines. In all, twenty-five molecules, including intermediates, were investigated for their in vitro anticancer activity, of which fourteen azaphenothiazines (2b, 3a, 3c, 3d, 3e-h, 3j, 3n, 3o, 3p, 3s, and 3u) were found to decrease the metabolic viability and growth of the T98G, H460 and SNU80 cancer cells effectively in a dose-dependent manner. In silico, pharmacokinetic studies suggest that these molecules have good bioavailability, water solubility and other drug-like parameters. Compounds 3a, 3c and 3g were identified as the leading molecules for future investigation due to their (a) high activity against T98G brain, H460 lung and SNU80 thyroid cancer cells; (b) low cytotoxicity with regard to non-malignant HEK293 and MRC5 cells; (c) low toxic risk levels based on in vitro and in silico evaluations; (d) good theoretical oral bioavailability according to Lipinski 'rule of five' pharmacokinetic parameters; and (e) better drug-likeness and drug-score values.
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India.
authors.forename: Khushbu
authors.initials: K
authors.lastname: Kushwaha
authors.affiliation: Plasma Bioscience Research Center, Department of Electrical and Biological Physics, Kwangwoon University, Seoul 139701, Republic of Korea.
authors.forename: Nagendra Kumar
authors.initials: NK
authors.lastname: Kaushik
authors.affiliation: Plasma Bioscience Research Center, Department of Electrical and Biological Physics, Kwangwoon University, Seoul 139701, Republic of Korea.
authors.forename: Neha
authors.initials: N
authors.lastname: Kaushik
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Chand
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India.
authors.forename: Reena
authors.initials: R
authors.lastname: Kaushik
authors.affiliation: Plasma Bioscience Research Center, Department of Electrical and Biological Physics, Kwangwoon University, Seoul 139701, Republic of Korea.
authors.forename: Eun Ha
authors.initials: EH
authors.lastname: Choi
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India. Electronic address: jainsc48@hotmail.com.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Jain
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006801:Humans; D010640:Phenothiazines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010640:Phenothiazines; C000609170:azaphenothiazine
keywords: Anticancer; Azaphenothiazines; Pharmacokinetic; Selective mono-alkylation; Toxicity risk