Design, synthesis and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives as selective c-Met inhibitors

Two novel series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives bearing 1H-imidazole-4-carboxamido or (E)-3-hydrosulfonylacrylamido motifs (16-31 and 32-42) were designed, synthesized and evaluated for their in vitro cytotoxic activity. Most of the compounds exhibited moderate to excellent potency against tested three cell lines, and fifteen compounds were further examined for their inhibitory activity against c-Met kinase. The most promising compound 16 (c-Met kinase [IC₅₀]=1.1nM) demonstrated high selectivity and remarkable cytotoxicity against HT-29, MKN-45 and A549 cells with IC₅₀ values of 0.08, 0.22 and 0.07μM, which were 3.1-, 1.4- and 2.1-fold more active than Foretinib. The preliminary structure-activity relationships as well as molecular docking disclosed that 1H-imidazole-4-carboxamido as a linker was of great importance for the antitumor activity.