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.

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 IC50 (0.029-0.087 µM) compared to reference drug sorafenib IC50 = 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 IC50 (0.073-0.196 µM) and (0.20-0.21 µM), respectively, relative to sorafenib IC50 0.16 and 0.19 µM, respectively. Compound 2f exhibiting a superior VEGFR-2 inhibition (IC50 = 0.029 µM compared to sorafenib IC50 = 0.091 µM) and cytotoxicity against MCF-7 and HepG2 (IC50 = 0.073 µM and IC50 = 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.