Synthesis and Biological Evaluation of 4‐Phenoxy‐6,7‐disubstituted Quinolines Possessing Semicarbazone Scaffolds as Selective c‐Met Inhibitors

ABSTRACT Novel quinoline derivatives bearing acyclic semicarbazones were prepared and their chemical structures as well as the relative stereochemistry were confirmed. All the synthesized compounds were evaluated for their c‐Met kinase inhibitory activity and their cytotoxicity against the cell lines HT‐29, MKN‐45, and MDA‐MB‐231 in vitro . Several potent compounds were further evaluated against A549 cells. Most compounds displayed moderate to excellent activity, and the structure–activity relationship studies identified the most promising compound 35 as a selective c‐Met kinase inhibitor (IC 50 = 4.3 nM). Compound 35 showed a 3.5‐ and 18.8‐fold increase in cytotoxicity in vitro against HT‐29 and A549 cells, respectively, compared to that of foretinib. Poor off‐target effects of compound 35 were further confirmed by the antiproliferative activity against the c‐Met inhibition less sensitive MDA‐MB‐231 cell line (IC 50 = 0.77 µM).