New chromene derivatives as promising VEGFR-2 inhibitors: combined experimental, DFT, and molecular dynamics approaches

Aims This study aimed to design and synthesize a novel series of chromene derivatives as potential vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors with anticancer activity.Materials and methods Chromene derivatives were synthesized and evaluated for in vitro cytotoxicity against cancer cell lines (MCF-7, MDA-MB-231, HepG-2, and HCT-116) and normal cells (WI-38 and WISH). VEGFR-2 inhibitory activity was determined. Mechanistic studies included wound healing assays, cell cycle analysis, apoptosis evaluation, and expression analysis of apoptosis-related markers. Molecular docking and 200 ns molecular dynamics simulations with MM-GBSA, Protein-Ligand Interaction Fingerprinting (Pro-LIF), Principal Component Analysis (PCA), and Free Energy Landscape (FEL) analyses were performed to assess ligand-protein interactions and complex stability.Results Compound 16 showed the highest activity with a VEGFR-2 IC50 of 1.175 ± 0.024 µM and selective cytotoxicity comparable to sorafenib while exhibiting low toxicity toward normal cells. It significantly inhibited cell migration, induced G0/G1 cell cycle arrest, and promoted apoptosis in HCT-116 cells, with increased Bax, caspase-3, and caspase-8 expression and reduced Bcl-2 levels. Computational analyses confirmed stable binding within the VEGFR-2 ATP-binding pocket. Conclusions: Compound 16 is a promising chromene-based VEGFR-2 inhibitor with potent antiproliferative and pro-apoptotic effects, supporting further in vivo investigation.