Discovery of N-(2-phenyl-1H-benzo[d]imidazol-5-yl)quinolin-4-amine derivatives as novel VEGFR-2 kinase inhibitors.

Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. In this work, a series of N-(2-phenyl-1H-benzo[d]imidazol-5-yl)quinolin-4-amine derivatives were designed and identified as potent inhibitors of VEGFR-2 (KDR) kinase. These compounds with quinoline scaffold and benzimidazole moiety were synthesized and their biological activities against VEGFR-2 and two human cancer cell lines were evaluated. Among them, compound 7s exhibited the most potent inhibitory activity against VEGFR-2 with IC50 of 0.03 μM and it also showed the highest anticancer activity against the tested cancer cell lines with IC50 of 1.2 μM against MCF-7 and 13.3 μM against Hep-G2. 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 7s is a potential agent for cancer therapy deserving further researching.