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The vascular endothelial growth factor receptor 2 (VEGFR2) is considered as a significant target for inhibition in the discovery of novel molecules with anti-proliferative activity. Here, we report the synthesis of novel derivatives of 1,2,4-triazole as potent VEGFR2 inhibitors with anti-HCC activity. The chemical structures of the target triazole derivatives were assured through elemental and spectral analysis. The in vitro anti-VEGFR2 activity of the new compounds was evaluated. Most compounds revealed promising inhibitory activity in comparison to Sorafenib (IC50= 0.088 µM). The triazolothiadiazine derivative 7a was the most active one (IC50= 0.057 µM). Also, the phenylhydrazono triazole derivatives 11c, 13b, and 13c showed potent activities (IC50= 0.074–0.124 µM) that were comparable to that of Sorafenib. Moreover, the anti-proliferative activity of most active compounds was assessed against two HCC cell lines and against normal hepatic cells THLE3. Compound 7a showed superior activity to Sorafenib; 2 times its activity against HepG2 and 15.5 times against Huh7. Furthermore, compound 13c was comparable to sorafenib against HepG2 and 4.1 times against Huh7. Besides, these potent compounds displayed higher safety profiles than Sorafenib against the normal THLE3 cells. In addition, docking simulation demonstrated good fitting with strong binding interactions within the VEGFR2 ATP binding site. In silico ADME calculations showed good GI absorption and high oral bioavailability of compound 7a. |
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