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

Abstract

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 μM, 0.15 ± 0.08 μM and 2.85 ± 0.74 μM, 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.