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

• 21 Novel quinolin-4-amines containing benzimidazole moiety were synthesized.
• The anticancer activities and inhibitory activities of VEGFR-2 were evaluated.
• The primary structure–activity relationships were discussed.
• Compound 7s exhibited the most potent inhibitory activities against VEGFR-2.
• Compound 7s also showed potent anticancer activities against MCF-7 and Hep-G2.

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.

A series of quinolin-4-amine derivatives containing benzimidazole moiety were discovered as potent inhibitors of VEGFR-2. Compound 7s exhibited the most potent inhibitory activity with IC50 of 0.03 μM against VEGFR-2.Figure optionsDownload as PowerPoint slide