Discovery of novel pyrrolo-pyridine/pyrimidine derivatives bearing pyridazinone moiety as c-Met kinase inhibitors

• DOI: 10.1016/j.ejmech.2017.10.027
• Publication Date: 2017-10-14T00:31:17Z
• Authors: Lin Xiao Wang; Xiaobo Liu; Shan Xu; Qidong Tang; Yongli Duan; Zhen Xiao; Jia Zhi; Liwen Jiang; Pengwu Zheng; Wufu Zhu
• Keywords: 0301 basic medicine; Dose-Response Relationship, Drug; Molecular Structure; Pyridines; Antineoplastic Agents; Apoptosis; Proto-Oncogene Proteins c-met; 3. Good health; Molecular Docking Simulation; Pyridazines; Structure-Activity Relationship; 03 medical and health sciences; Pyrimidines; Cell Line, Tumor; Drug Discovery; Humans; Pyrroles; Drug Screening Assays, Antitumor; Protein Kinase Inhibitors; Cell Proliferation

In continue to our previous research, eight series of pyrrolo[2,3-b]pyridine and pyrrolo[2,3-d]pyrimidine derivatives bearing pyridazinone moiety were designed, synthesized, and the in vitro antitumor activity was evaluated against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). Some selected compounds (22f, 22g, 26c and 26e) were evaluated for the activity against c-Met kinase, and according to the results of kinase inhibitory activity, the compound 22g was further evaluated for other four tyrosine kinases (Flt-3, VEGFR-2, c-Kit and EGFR) to test the enzyme-based selectivity. The most promising compound 22g showed excellent activity than lead compound Foretinib against A549, HepG2, MCF-7 and PC-3 cell lines, with the IC50 values of 2.19 ± 0.45 μM, 1.32 ± 0.26 μM, 6.27 ± 1.04 μM and 4.63 ± 0.83 μM. The structure-activity relationships (SARs) and docking studies indicated that the pyrrolo[2,3-b]pyridine derivatives bearing 4-oxo-pyridazinone moiety was superior to the pyrrolo[2,3-d]pyrimidine derivatives bearing 6-oxo-pyridazinone moiety. What's more, the target compounds modified with X and Y (X = H, Y = H) were favorable to the activity. And electron drawing groups (EWGs) of 4-Cl-3CF3 on the aryl group show the best activity.