Design, synthesis and biological evaluations of novel VEGFR-2 inhibitors based on Fruquintinib and Cabozantinib.

In this study, two series of VEGFR-2 inhibitors were designed based on the Fruquintinib and Cabozantinib. Series 1 compounds retained the quinazoline skeleton and amide group of Fruquintinib, while the benzofuran moiety was replaced with a coumarin moiety, and various substituents were introduced at the amide N-terminus to explore structure-activity relationships (SARs). Series 2 compounds were derived from Cabozantinib by incorporating a rigid pyridine linker via conformational constraint and replacing the terminal phenyl group with bicyclo[1.1.1]pentane (BCP). All target compounds were evaluated for their VEGFR-2 inhibitory activity. Among series 1, compound 20 showed the significant inhibitory activity with an IC₅₀ value of 85.35 nM. Notably, series 2 compounds demonstrated significantly improved potency, with IC50 values below 30 nM. Compound 32 was the most potent VEGFR-2 inhibitor with an IC50 value of 7.52 nM, while its IC50 values for VEGFR-1 and VEGFR-3 were 74.41 and 5.63 nM, respectively. In vitro antiproliferative assays revealed that several series 2 compounds, including 32, displayed more potent antiproliferative activity against A549 cells than Cabozantinib. Molecular docking studies elucidated the binding mode of compound 32, highlighting key hydrogen bond with the hinge region of VEGFR-2. Collectively, compound 32 emerges as a promising lead compound for further optimization as a novel VEGFR-2 inhibitor.