Design, synthesis, biological evaluation, and molecular modeling study of 4-alkoxyquinazoline derivatives as potential VEGFR2 kinase inhibitors

A series of novel 4-alkoxyquinazoline derivatives were prepared and synthesized and their biological activities were evaluated as potential inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2/KDR/Flk-1). Of these compounds, compound 3j demonstrated the most potent inhibitory activities against VEGFR2/KDR/Flk-1 tyrosine kinase and cell proliferation, the IC50 values of this compound reaching up to 2.72 nM and 0.35 μM, respectively, compared with Tivozanib (3.40 nM and 0.38 μM). The obtained results, along with a 3D-QSAR study and molecular docking that was used for investigating the probable binding mode, could provide an important basis for further optimization of compound 3j as a potential tyrosine kinase inhibitor.