Design, synthesis and structure–activity relationships of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety as potential antitumor agents

• A series of 4-phenoxyquinoline derivatives containing pyridazinone moiety were designed and synthesized.
• The target compounds showed potent antitumor activity.
• Six compounds were further examined for their c-Met kinase activity.
• The cytotoxicity of 15a was 2.3-fold higher against A549 cells than foretinib.
• Compound 15a showed an IC50 value of 2.15 nM against c-Met kinase.

A series of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (HT-29, H460, A549, MKN-45, and U87MG). Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines. Compounds 15a, 20a, 15b, 15c, 20d, and 16e were further examined for their inhibitory activity against c-Met kinase. The most promising compound 15a (c-Met half-maximal inhibitory concentration [IC50] = 2.15 nM) showed remarkable cytotoxicity against HT-29, H460, and A549 cell lines with IC50 values of 0.10 μM, 0.13 μM, and 0.05 μM, respectively, and thus it was 1.5- to 2.3-fold more potent than foretinib. Their preliminary structure–activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.

A series of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety were synthesized and evaluated for their cytotoxic activities. Six potent compounds were further examined for their c-Met kinase activity.Figure optionsDownload as PowerPoint slide