Evaluation of oxadiazole-N-phenylacetamide conjugates as VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative assessment, molecular docking, and dynamics studies.

AIM: A novel series of oxadiazole-based derivatives was designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors.

METHOD: The synthesized compounds were evaluated for their cytotoxic and VEGFR-2 inhibition activities.

RESULTS: Compound 11i was a super cytotoxic member, showing IC50 of 3.26 and 5.11 µM, twice as active as sorafenib (IC50 = 8.83 and 6.68 µM) against hepatocellular carcinoma (HepG2) and colon cancer (HCT-116), respectively. Also, the VEGFR-2 inhibitory assay revealed that derivative 11i was the most potent VEGFR-2 inhibitor, showing a strong IC50 value of 0.56 nM, compared to sorafenib (IC50 = 0.46 nM). Furthermore, extra mechanistic studies were conducted on the most active candidate 11i. The results indicated that such a compound arrested the cell cycle at both S and G2/M stages, triggering apoptosis in HepG2 cells. Also, compound 11i produced a significant increase in the expression levels of apoptotic suppressors, caspase-3 and BAX, and a significant reduction of apoptosis motivator, Bcl-2 protein. Moreover, docking and molecular dynamics (MD) simulation studies revealed the correct binding mode and the optimum dynamics of compound 11i inside the VEGFR-2 pocket.

CONCLUSION: This study represents compound 11i, incorporating an oxadiazole scaffold as a promising VEGFR-2 inhibitor with potent anticancer activity.