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…
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