New 5-(pyridin-3-yl)-1,3,4-oxadiazoles derivatives as VEGFR2 inhibitors: in silico study, synthesis, and cytotoxicity evaluation.

Abstract

Background and purpose: Angiogenesis, regulated by vascular endothelial growth factor receptor 2 (VEGFR-2), has a key role in tumor progression, especially in common cancers, including colorectal and renal cancer. Inhibiting VEGFR-2 is a promising therapeutic approach. This research aimed to design, synthesize, and biologically evaluate new 5-(pyridine-3-yl)-1,3,4-oxadiazole derivatives as potential VEGFR-2 inhibitors.

Experimental approach: A new series of derivatives (AM3-AM6) was synthesized through S-alkylation of 5-(pyridin-3-yl)-1,3,4-oxadiazole-2-thiol and hydrazinolysis reactions, followed by condensation with aldehydes. The compounds were analyzed using FT-IR,¹H-NMR, and ¹³C-NMR spectroscopy. Molecular modelling studies, including docking (PDB ID: 4ASD), ADMET prediction, and molecular dynamics (MD) simulations, were performed to evaluate binding affinity, pharmacokinetic properties, and complex stability. Cytotoxicity was assessed via MTT assay against HT-29 (colorectal), ACHN (renal), and L929 (normal) cell lines.

Findings/results: Docking results revealed strong binding to VEGFR-2, with compound AM3 showing the best docking score (ΔG = -11.613 kcal/mol). MD simulations confirmed the high stability of the AM3-VEGFR-2 complex with consistent RMSD values and persistent interactions with GLU885 and ASP1046. In vitro, AM4 exhibited a significant cytotoxic effect against HT-29 cells (IC₅₀ = 38.94 μM), compared to sorafenib (IC₅₀ = 9.73), while all compounds were non-toxic toward L929 cells.

Conclusions and implications: In silico and in vitro results demonstrated that the new 5-(pyridine-3-yl)-1,3,4-oxadiazole derivatives possess favorable drug-like properties and selective anti-proliferative activity against colorectal and renal cancer cells. These findings suggest that this scaffold is a valuable starting point for developing novel selective VEGFR-2 inhibitors as anticancer agents.