Discovery of new thiadiazole-based VEGFR-2 inhibitors: design, synthesis, cytotoxicity, and apoptosis induction
Eslam B. Elkaeed, Walid E. Elgammal, Hazem Elkady, Hazem A. Mahdy, Aisha A. Alsfouk, Dalal Z. Husein, Omar Soliman, Mariam Omara, Ibrahim H. Eissa, Ahmed M. Metwaly
Abstract
BACKGROUND: Vascular endothelial growth factor receptor-2 (VEGFR-2) is a validated target in cancer therapy. However, approved inhibitors like sorafenib are often limited by off-target toxicity and resistance. This study aimed to develop novel thiadiazole-based VEGFR-2 inhibitors with improved selectivity and safer profiles. METHODS: A series of 2,3-dihydro-1,3,4-thiadiazole derivatives was rationally designed, synthesized, and structurally characterized. In vitro cytotoxicity was assessed against MCF-7, HepG-2, HCT-116, and normal WI-38 cells. Mechanistic assays included flow cytometry for cell cycle and apoptosis, and ELISA for caspase-3, Bcl-2, and Bax expression. Molecular docking, 200-ns molecular dynamics (MD) simulations, density functional theory (DFT) calculations, and in silico toxicity profiling supported experimental findings. RESULTS: Compound 11a exhibited the most potent and selective activity (IC₅₀: 9.49 µM for MCF-7, 12.89 µM for HepG-2; SI > 3). It induced >70% apoptosis and dual-phase (S and G2/M) cell cycle arrest. VEGFR-2 inhibition (IC₅₀ = 0.055 µM) was comparable to sorafenib. Computational studies confirmed stable binding at VEGFR-2 active sites. CONCLUSION: Compound 11a is a promising thiadiazole-based candidate with notable in vitro potency, selectivity, and mechanistic activity, supporting its potential for further pharmacokinetics/toxicity evaluation and structural refinement as a VEGFR-2-targeted agent.