New Chromene Derivatives as Promising VEGFR‐2 Inhibitors: Experimental Cytotoxicity and Comprehensive Computational Characterization

Abstract

A new series of chromene derivatives (12–19) was rationally designed as potential inhibitors of vascular endothelial growth factor receptor‐2 (VEGFR‐2) by integrating essential pharmacophoric and structural features. The target compounds were synthesized and structurally confirmed using spectroscopic techniques. Their in vitro antiproliferative activities were evaluated against a panel of human cancer cell lines (MCF‐7, MDA‐MB‐231, HepG‐2, and HCT‐116) alongside normal human cells (WI‐38 and WISH), in addition to a VEGFR‐2 enzyme inhibition assay. Among the synthesized derivatives, compound 17 emerged as the most potent candidate, displaying low micromolar IC50 values across all tested cancer cell lines and superior VEGFR‐2 inhibitory activity (IC50 = 0.518 µM) compared with the reference drug sorafenib (IC50 = 0.809 µM). Mechanistic investigations revealed that compound 17 induced pronounced cell cycle arrest and triggered apoptosis, as demonstrated by Annexin V–FITC/PI flow cytometric analysis. Computationally, Density Functional Theory (DFT) calculations demonstrated favorable electronic properties for compound 17, supporting effective ligand–receptor interactions. Molecular docking and 100‐ns molecular dynamics (MD) simulations, complemented by MM‐GBSA binding free energy calculations, Protein–Ligand Interaction Fingerprinting (Pro‐LIF), Principal Component Analysis (PCA‐T), and Free Energy Landscape (FEL) analyses, confirmed the stability and favorable binding energetics of compound 17 within the VEGFR‐2 active site. Furthermore, in silico ADME–Tox profiling predicted acceptable pharmacokinetic behavior and a favorable safety profile. Collectively, these experimental and computational findings identify compound 17 as a promising and mechanistically well‐characterized VEGFR‐2 inhibitor, warranting further in vivo investigation.