Discovery of new thiadiazole-based VEGFR-2 inhibitors: design, synthesis, cytotoxicity, and apoptosis induction.

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.