Design, Synthesis, and Biological Evaluation of [1,2,4]triazolo[4,3-a] Pyrazine Derivatives as Novel Dual c-Met/VEGFR-2 Inhibitors

In this study, we designed and synthesized a series of novel [1,2,4]triazolo [4,3- a ]pyrazine derivatives, and evaluated them for their inhibitory activities toward c-Met/VEGFR-2 kinases and antiproliferative activities against tested three cell lines in vitro . Most of the compounds showed satisfactory activity compared with lead compound foretinib. Among them, the most promising compound 17l exhibited excellent antiproliferative activities against A549, MCF-7, and Hela cancer cell lines with IC 50 values of 0.98 ± 0.08, 1.05 ± 0.17, and 1.28 ± 0.25 µM, respectively, as well as excellent kinase inhibitory activities (c-Met IC 50 = 26.00 nM and VEGFR-2 IC 50 = 2.6 µM). Moreover, compound 17l inhibited the growth of A549 cells in G0/G1 phase in a dose-dependent manner, and induced the late apoptosis of A549 cells. Its intervention on intracellular c-Met signaling of A549 was verified by the result of Western blot. Fluorescence quantitative PCR showed that compound 17l inhibited the growth of A549 cells by inhibiting the expression of c-Met and VEGFR-2, and its hemolytic toxicity was low. Molecular docking and molecular dynamics simulation indicated that compound 17l could bind to c-Met and VEGFR-2 protein, which was similar to that of foretinib.