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.