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Abstract Study involves design and synthesis of five series of 6-bromo2-(pyridin-3-yl)-4-substituted quinazolines Xa-l, XIa-e, XIIa-c, XIIIa-f and XIVae. Candidates Xa-l and XIa-e were evaluated for their EGFR and HER2 inhibitory activity compared to Lapatinib. Compounds Xb, Xd, Xf, XIb and XIc 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 Xd revealed a remarkable cytotoxic efficacy against AU-565 cell line (IC50 = 1.54 μM) relative to Lapatinib (IC50 = 0.48 μM), whereas compounds Xd and XIc 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 XIIa-c, XIIIa-f and XIVa-e were tested for their VEGFR-2 inhibitory activity compared to Sorafenib. Compounds XIIa, XIIIc and XIIIe 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 XIIa (IC50 = 17.51 and 5.56 μM, respectively) and XIIIc (IC50 = 10.40 and 3.37 μM, respectively) compared to Sorafenib (IC50 = 19.33 and 6.82 μM, respectively). Compounds Xd, XIc and XIIIc 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. |