Design, synthesis and biological evaluation of quinoline amide derivatives as novel VEGFR-2 inhibitors

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in the process of cancer angiogenesis. A series of quinoline amide derivatives were prepared and found to be good inhibitors of VEGFR-2. The inhibitory activities were investigated against VEGFR-2 kinase and human umbilical vein endothelial cells (HUVEC) in vitro. Compound 6 (5-chloro-2-hydroxy-N-(quinolin-8-yl)benzamide) exhibited the most potent inhibitory activity (IC50 = 3.8 and 5.5 nM for VEGFR-2 kinase and HUVEC, respectively). Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the ATP-binding site of VEGFR-2, which demonstrates that compound 6 is a potential agent for cancer therapy deserving further researching.

Graphical abstractTwo series of quinoline amide derivatives were prepared and found to be good inhibitors of vascular endothelial growth factor receptor-2 (VEGFR-2). The inhibitory activities were investigated against VEGFR-2 kinase and human umbilical vein endothelial cells (HUVEC) in vitro. Compound 6 (5-chloro-2-hydroxy-N-(quinolin-8-yl)benzamide) exhibited the most potent inhibitory activity (IC50 = 3.8 and 5.5 nM for VEGFR-2 kinase and HUVEC, respectively). Docking simulation was performed to position compound 6 into the VEGFR-2 ATP-binding site to determine the probable binding model. The results supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the ATP-binding site of VEGFR-2.Figure optionsDownload full-size imageDownload as PowerPoint slide