Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety

Abstract A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety were designed, synthesized and evaluated for their biological activities. The target compounds exhibited moderate to high antiproliferative activity against three cancer cell lines (A549, HepG2 and MCF-7) and several compounds ( 25 , 27 , 33 , 37 , 41 , 43 , 49 and 53 ) were evaluated for the activity against c-Met kinase. The most promising compound 33 (IC 50 c-Met = 2.36 nM) showed excellent activity against A549, HepG2 and MCF-7 cell lines with IC 50 values of 0.23 μM, 0.42 μM and 0.21 μM, respectively, which was 1.5–2.1 times of the positive control. Furthermore, compound 33 was evaluated for the activity against Flt3, PDGFR-α, PDGFR-β, c-Kit, Flt4, ALK and EGFR kinase. Structure activity relationship studies indicated that mono-EWGs (such as R 2  = F) at 4-position of moiety C was a key factor in improving the antitumor activity. In addition, further research on compound 33 was mainly including concentration dependence, apoptosis (acridine orange staining), apoptosis result analyzing and molecular docking.