Three series of novel 4-phenoxypyridine derivatives containing 4-methyl-6-oxo-1,6-dihydropyridazine- 3-carboxamide, 5-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide and 4-methyl-3,5-dioxo-2,3,4,5- tetrahydro-1,2,4-triazine-6-carboxamide moieties were synthesized and evaluated for their in vitro inhibitory activitives against c-Met kinase and cytotoxic activitives against A549, H460, HT-29 cancer cell lines. The results indicated that most of the compounds showed moderate to good antitumor activitives. The most promising compound 26a (with c-Met IC50 value of 0.016 μM) showed remarkable cytotoxicity against A549, H460, and HT-29 cell lines with IC50 values of 1.59 μM, 0.72 μM and 0.56 μM, respectively. Their preliminary structure-activity relationships (SARs) studies indicate that 4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide was more preferred as linker part, and electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activitives. Furthermore, the colony formation, acridine orange/ethidium bromide (AO/EB) staining, apoptosis, and wound-healing assay of 26a were performed on HT-29 and/or A549 cell lines.
Keywords: 4-Phenoxypyridine derivatives; Antitumor activity; Docking study; Synthesis; c-Met inhibitors.
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