Zhang, Qian Liu, Xiaobo Gan, Wenhui Wu, Jinjin Zhou, Hualan Yang, Zunhua Zhang, Yiling Liao, Min Yuan, Ping Xu, Shan Zheng, Pengwu Zhu, Wufu Discovery of Triazolo-pyridazine/-pyrimidine Derivatives Bearing Aromatic (Heterocycle)-Coupled Azole Units as Class II c‑Met Inhibitors 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 <i>in vitro</i>. The pharmacological data indicated that most of the tested compounds showed moderate cytotoxicity, and the most promising compound <b>12e</b> exhibited significant cytotoxicity against A549, MCF-7, and HeLa cell lines with IC<sub>50</sub> values of 1.06 ± 0.16, 1.23 ± 0.18, and 2.73 ± 0.33 μM, respectively. Moreover, the inhibitory activity of compound <b>12e</b> against c-Met kinase (IC<sub>50</sub> = 0.090 μM) was equal to that of Foretinib (IC<sub>50</sub> = 0.019 μM). The result of the acridine orange (AO) single staining test demonstrated that compound <b>12e</b> could remarkably induce apoptosis of A549 cells. The results of apoptosis and cycle distribution of cells showed that compound <b>12e</b> 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 <b>12e</b> may become a potential class II c-Met inhibitor. 5- methylthiazole fragment;compound 12 e;0.090 μ M;IC 50 values;c-Met kinase;HeLa cell lines;class II c-Met inhibitor;hepatocytes cell line LO 2;0.019 μ M;SAR;apoptosi;549 cells;IC 50;c-Met overexpressed cancer cell lines;AO;MCF 2020-06-30
    https://acs.figshare.com/articles/journal_contribution/Discovery_of_Triazolo-pyridazine_-pyrimidine_Derivatives_Bearing_Aromatic_Heterocycle_-Coupled_Azole_Units_as_Class_II_c_Met_Inhibitors/12585370
10.1021/acsomega.0c00838.s001