Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies.

A library of modified VEGFR-2 inhibitors was designed as VEGFR-2 inhibitors. Virtual screening was conducted for the hypothetical library using docking, ADMET, and toxicity studies. Four compounds exhibited high affinity against VEGFR-2 and an acceptable range of the drug-likeness. These compounds were synthesised and subjected to cytotoxicity assay against two cancer cell lines besides VEGFR-2 inhibitory determination. Compound showed cytotoxic activity against HCT-116 cells almost double that of sorafenib. Compounds , , and showed good IC values against VEGFR-2. Compound markedly increased the levels of caspase-8 and BAX expression and decreased the anti-apoptotic Bcl-2 level. Additionally, compound caused cell cycle arrest at pre-G1 and G2-M phases in HCT-116 cells and induced apoptosis at both early and late apoptotic stages. Compound decreased the level of TNF-α and IL6 and inhibited TNF-α and IL6. MD simulations studies were performed over 100 ns.