Abstract

1,3,4-oxadiazole represents a versatile scaffold for innovative drug development. The isomer received considerable attention due to its distinctive bioisosteric characteristics, favorable physicochemical stability. In this study, eight oxadiazole derivatives (1D–8D) were synthesized and structurally characterized by Infrared spectroscopy, mass spectrometry, and H1 nuclear magnetic resonance. Molecular docking against vascular endothelial growth factor receptor II (VEGFR-II) revealed favorable binding, with compound 4D showing the best docking score (–8.158 kcal/mol) compared with the standard drug sorafenib (–5.62 kcal/mol). In vitro cytotoxicity evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay demonstrated that 4D had IC50values of 22.9 μg/ml (PA-1), 29.5 μg/ml (MCF-7), and 39.6 μg/ml (A-549), while displaying minimal toxicity in HEK293 normal cells (IC50> 100 μg/ml), resulting in a selectivity index (SI) >3. The anti-angiogenic potential of 4D was confirmed in the chick chorioallantoic membrane assay. Molecular dynamics simulations further supported stable interactions of 4D with VEGFR-II. Collectively, these findings identify compound 4D as a novel scaffold with moderate anticancer activity and improved selectivity compared to sorafenib, identifying it as a promising lead scaffold for further optimization as a potential VEGFR-2 inhibitor.

Key words: 1,3,4-oxadiazole, VEGFR-II inhibition, anticancer activity, MTT assay, CAM assay, molecular docking, MD simulation