2. Academic Validation
  3. Design, synthesis and biological evaluation of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment

Design, synthesis and biological evaluation of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment

  • Bioorg Med Chem Lett. 2020 May 1;30(9):127076. doi: 10.1016/j.bmcl.2020.127076.
Hehua Xiong 1,  Jianqing Zhang 1,  Qian Zhang 1,  Yongli Duan 2,  Han Zhang 1,  Pengwu Zheng 3,  Qidong Tang 4
Affiliations

Affiliations

  • 1 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
  • 2 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China; School of Optoelectronic Science and Engineering, University of Electronic Science and Technology of China (UESTC), Chengdu 610054, PR China.
  • 3 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China. Electronic address: zhengpw@126.com.
  • 4 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China. Electronic address: tangqidongcn@126.com.
PMID: 32173195 DOI: 10.1016/j.bmcl.2020.127076
Abstract

A series of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment were designed, synthesized, and evaluated for their biological activity. Most compounds showed effective inhibitory activity against Cancer cell lines of A549, HeLa and MCF-7. Among them, the most promising compound 40 showed excellent activity against A549, HeLa and MCF-7 cell lines with IC50 values of 1.03, 1.15 and 2.59 μM, respectively, which was 2.606.95 times more active than that of Golvatinib. The structure-activity relationships (SARs) showed that the introduction of 5-methylpyridazin-3(2H)-one to "5-atom linker" and the modification of the amide with morpholine group were beneficial for enhancing the inhibitory activity of compounds. In addition, the further research on compound 40 mainly include c-Met kinase activity, concentration dependence, Apoptosis (acridine orange staining), and molecular docking.

Keywords

4-(Pyridin-4-yloxy)benzamide derivatives; 5-Methylpyridazin-3(2H)-one; Inhibitors; Synthesis; c-Met.

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