Discovery of [1,2,4]triazolo[4,3-a]pyrazine derivatives bearing a 4-oxo-pyridazinone moiety as potential c-Met kinase inhibitors

Two series of [1,2,4]triazolo[4,3-a]pyrazine derivatives bearing 4-oxo-pyridazinone moieties (compounds 21a-l and 22a-l) were designed and their IC50 values were evaluated against three cancer cell lines (A549, MCF-7 and HeLa) and c-Met kinase. Among them, the compound with most potential, 22i, exhibited excellent anti-tumor activity against A549, MCF-7 and HeLa cancer cell lines with IC50 values of 0.83 +/- 0.07 mu M, 0.15 +/- 0.08 mu M and 2.85 +/- 0.74 mu M, respectively, and it also possessed superior c-Met kinase inhibition ability at the nanomolar level (IC50 = 48 nM). Moreover, dose-dependent experiments, AO fluorescence staining, cell cycle assay, Annexin V-FITC/PI staining and docking studies were carried out in this study. The results demonstrated that compound 22i could be a potential c-Met kinase inhibitor.