Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents

• Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives were designed and synthesized.
• Five compounds were further examined for their c-Met kinase activity.
• Compound 17 showed an IC50 values of 2.20 nM against c-Met kinase.

Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against HT-29, H460, A549, MKN-45, and U87MG cancer cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant cytotoxicity and high selectivity against HT-29, H460 and A549 cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially trifluoromethyl groups at 2-position on the phenyl ring (moiety B) were more effective. In this study, a promising compound 17 (c-Met IC50 = 2.20 nM, a multi-target tyrosine kinase inhibitor) showed the most potent antitumor activities with IC50 values of 0.14 μM, 0.18 μM, 0.09 μM, 0.03 μM, and 1.06 μM against HT-29, H460, A549, MKN-45, and U87MG cell lines, respectively.

Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were synthesized and evaluated for their cytotoxic activities. Five potent compounds were further examined for their c-Met kinase activity.Figure optionsDownload as PowerPoint slide