Novel aminoalkylated azaphenothiazines as potential inhibitors of T98G, H460 and SNU80 cancer cell lines in vitro

• Published in: Bioorganic & medicinal chemistry letters 2016-05, Vol.26 (9), p.2237-2244
• Main Authors: Kushwaha, Khushbu, Kaushik, Nagendra Kumar, Kaushik, Neha, Chand, Mahesh, Kaushik, Reena, Choi, Eun ha, Jain, Subhash C.
• Format: Article
• Language: English
• Subjects: Anticancer; Antineoplastic Agents - pharmacology; Azaphenothiazines; Drug Screening Assays, Antitumor; HEK293 Cells; Humans; Pharmacokinetic; Phenothiazines - pharmacology; Selective mono-alkylation; Structure-Activity Relationship; Toxicity risk
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.03.056

[Display omitted] 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.