Design, synthesis, and biological evaluation of novel 4-phenoxypyridine derivatives as potential antitumor agents

A series of novel 4-phenoxypyridine derivatives containing the 4-oxo-1,4-dihydropyridazine-3-carboxamide moiety were synthesized and evaluated for their in vitro cytotoxic activity against the A549 cancer cell line, and some compounds were further examined for their cytotoxic activity against the H460, BGC823, MKN45, and HT-29 cancer cell lines. Most of the compounds exhibited moderate to significant cytotoxicity. The most promising compound 15b (with VEGFR2 inhibitory concentration [IC₅₀ ] value of 0.23 μM) showed remarkable cytotoxicity against A549, BGC-823, MKN45, H460, and HT-29 cells, with IC₅₀ values of 0.75, 1.68, 2.63, 5.08 and 7.22 μM, respectively. Their preliminary structure-activity relationship studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity. Moreover, treatment of A549 cells with compound 15b resulted in cell cycle arrest in the G₀ /G₁ phase in a dose-dependent manner. Further apoptotic studies and acridine orange/ethidium bromide staining were also performed on A549 cells, which showed that compound 15b could induce apoptosis. Wound-healing assay results indicated that compound 15b strongly inhibited A549 cell motility.