Design, Synthesis, In Vitro Biological Evaluation, and In Silico Studies of Novel Imidazo[4,5‐ b ]Pyridine‐Acrylonitrile‐Based Derivatives as VEGFR‐2 Inhibitors Against Breast Cancer and Hepatocellular Carcinoma

ABSTRACT Vascular endothelial growth factor receptor‐2 (VEGFR‐2) is a vital mediator of angiogenesis. Therefore, VEGFR‐2 inhibition is considered a promising therapeutic target to combat cancer. In the present study, a series of 22 imidazo[4,5‐ b ]pyridine‐acrylonitrile‐based derivatives was designed and synthesized. All compounds were evaluated for their VEGFR‐2 inhibitory activity. Seven of the tested compounds showed high inhibitory activity against VEGFR‐2 with IC 50 (0.029–0.087 µM) compared to reference drug sorafenib IC 50 = 0.091 µM. Four of these derivatives were selected for in vitro cytotoxic activity against breast cancer (MCF‐7) and hepatocellular (HepG2) carcinoma cell lines, showing IC 50 (0.073–0.196 µM) and (0.20–0.21 µM), respectively, relative to sorafenib IC 50 0.16 and 0.19 µM, respectively. Compound 2f exhibiting a superior VEGFR‐2 inhibition (IC 50 = 0.029 µM compared to sorafenib IC 50 = 0.091 µM) and cytotoxicity against MCF‐7 and HepG2 (IC 50 = 0.073 µM and IC 50 = 0.09 µM, respectively), was subjected to cell cycle analysis, apoptosis assay, and molecular modeling studies, which strongly supported the results. It caused cell cycle arrest at G2/M phase by 13.67% and a promising apoptosis induction. 2f exhibited a promising binding score and pose inside the VEGFR‐2 active sites. It also showed a good safety profile with a moderate selectivity index. Based on the prediction of physicochemical and pharmacokinetic properties for 2f , it showed excellent prediction results to be orally bioavailable.