Design, synthesis and biological evaluation of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties as c-Met kinase inhibitors

A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against H460, MKN-45, HT-29 and MDA-MB-231 Cancer cell lines in vitro. Most compounds displayed good to excellent potency against four tested Cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially fluoro groups at 4-position on the phenyl ring (moiety B) were more effective than those with nitro groups or methoxy groups. In this study, a promising compound 33 (c-Met IC50=1.63nM) was identified, which showed the most potent antitumor activities with IC50 values of 0.055μM, 0.071μM, 0.13μM, and 0.43μM against H460, MKN-45, HT-29 and MDA-MB-231 cell lines, respectively.

2-Phenylphthalazin-1(2H)-one; 4-Phenoxyquinoline derivatives; Antitumor activity; c-Met.