Design, synthesis, and structure–activity relationships of novel 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents

• Two series of quinoline derivatives were designed and synthesized.
• The target compounds showed potent antitumor activity.
• Seven compounds were further examined for their c-Met kinase activity.
• The cytotoxicity of 18b was 7.3-fold higher against HT-29 cells than foretinib.
• Compound 18b showed an IC50 value of 1.39 nM against c-Met kinase.

Two series of quinoline derivatives bearing the pyridine/pyrimidine scaffold were synthesized, and evaluated for their c-Met kinase inhibitory activity and antiproliferative activity against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) were evaluated in vitro. Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 18b (c-Met half-maximal inhibitory concentration [IC50] = 1.39 nM) showed a 7.3-fold increase in activity against HT-29 cell line in vitro. Structure–activity relationship studies indicated that regulation of the electron density on the pyridine/pyrimidine ring to a proper degree was a key factor in improving the antitumor activity.

Two series of quinoline derivatives bearing pyridine/pyrimidine scaffolds were synthesized and evaluated for their cytotoxic activities. Seven potent compounds were further examined for their c-Met kinase activity.Figure optionsDownload as PowerPoint slide