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=2.20nM, a multi-target tyrosine kinase inhibitor) showed the most potent antitumor activities with IC50 values of 0.14μM, 0.18μM, 0.09μM, 0.03μM, and 1.06μM against HT-29, H460, A549, MKN-45, and U87MG cell lines, respectively.
Keywords: 2,4-Imidazolinedione/pyrazolone; 4-Phenoxyquinoline derivatives; Anticancer activity; c-Met.
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