Two
series of novel triazolo-pyridazine/-pyrimidine derivatives
were designed, synthesized, and evaluated for their inhibitory activity
against c-Met kinase, as well as three c-Met overexpressed cancer
cell lines (A549, MCF-7, and HeLa) and one normal human hepatocytes
cell line LO2
in vitro
. The pharmacological data
indicated that most of the tested compounds showed moderate cytotoxicity,
and the most promising compound
12e
exhibited significant
cytotoxicity against A549, MCF-7, and HeLa cell lines with IC
50
values of 1.06 ± 0.16, 1.23 ± 0.18, and 2.73 ±
0.33 μM, respectively. Moreover, the inhibitory activity of
compound
12e
against c-Met kinase (IC
50
=
0.090 μM) was equal to that of Foretinib (IC
50
=
0.019 μM). The result of the acridine orange (AO) single staining
test demonstrated that compound
12e
could remarkably
induce apoptosis of A549 cells. The results of apoptosis and cycle
distribution of cells showed that compound
12e
could
induce late apoptosis of A549 cells and stimulate A549 cells arresting
in the G0/G1 phase. Structure–activity relationships (SARs),
pharmacological results, and docking studies indicated that the introduction
of 5-methylthiazole fragment to the five-atom moiety was beneficial
for the activity. So far, the existing data indicated that compound
12e
may become a potential class II c-Met inhibitor.