Abstract
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 IC(50) of 3.26 and 5.11 µM, twice as active as sorafenib (IC(50) = 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 11(i) was the most potent VEGFR-2 inhibitor, showing a strong IC(50) value of 0.56 nM, compared to sorafenib (IC(50) = 0.46 nM). Furthermore, extra mechanistic studies were conducted on the most active candidate 11(i). 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 11(i) 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 11(i) inside the VEGFR-2 pocket. CONCLUSION: This study represents compound 11(i,) incorporating an oxadiazole scaffold as a promising VEGFR-2 inhibitor with potent anticancer activity.