Design and synthesis of some new 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines as multi tyrosine kinase inhibitors

Abstract

The present study involves design and synthesis of five series of 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines 9a-l, 11a-e, 13a-c, 14a-f and 15a-e. Candidates 9a-l and 11a-e were evaluated for their EGFR and HER2 inhibitory activity compared to Lapatinib. Compounds 9b, 9d, 9f, 11b and 11c were further screened for their in vitro cytotoxicity against two human breast cancer cell lines: AU-565 and MDA-MB-231 in addition to normal breast cell line MCF10A. Compound 9d revealed a remarkable cytotoxic efficacy against AU-565 cell line (IC₅₀ = 1.54 µM) relative to Lapatinib (IC₅₀ = 0.48 µM), whereas compounds 9d and 11c showed a superior cytotoxicity towards MDA-MB-231 (IC₅₀ = 2.67 and 1.75 µM, respectively) in comparison to Lapatinib (IC₅₀ = 9.29 µM). Moreover, compounds 13a-c, 13a-c, 14a-f and 15a-e were tested for their VEGFR-2 inhibitory activity compared to Sorafenib. Compounds 13a, 14c and 14e exhibited remarkable inhibition (IC₅₀ = 79.80, 50.22 and 78.02 nM, respectively) relative to Sorafenib (IC₅₀ = 51.87 nM). In vitro cytotoxicity of these compounds against HepG2, HCT-116 and normal cell (WISH) revealed a superior cytotoxicity against HepG2, HCT-116 especially 13a (IC₅₀ = 17.51 and 5.56 µM, respectively) and 14c (IC₅₀ = 10.40 and 3.37 µM, respectively) compared to Sorafenib (IC₅₀ = 19.33 and 6.82 µM, respectively). Compounds 9d, 11c and 14c were subjected to cell cycle analysis and apoptotic assay. Molecular docking and ADME prediction studies were fulfilled to illustrate the interaction of the potent derivatives with the hot spots of the active site of EGFR, HER2 and VEGFR-2 along with prediction of their pharmacokinetic and physicochemical properties.

Keywords: Anticancer activity; Dual EGFR/HER2; EGFR; HER2; Quinazoline; VEGFR-2.