Novel aminoalkylated azaphenothiazines as potential inhibitors of T98G, H460 and SNU80 cancer cell lines in vitro. Issue 9 (1st May 2016)

• Record Type: Journal Article
• Authors: Kushwaha, Khushbu; Kaushik, Nagendra Kumar; Kaushik, Neha; Chand, Mahesh; Kaushik, Reena; Choi, Eun ha; Jain, Subhash C.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 9(2016)
• Page Start: 2237
• Page End: 2244
• Publication Date: 2016-05-01
• Subjects: Azaphenothiazines -- Selective mono-alkylation -- Anticancer -- Pharmacokinetic -- Toxicity risk; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.03.056
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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, and3u ) 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. Compounds3a, 3c and3g 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.