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. Epub 2020 Mar 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Survival
  • Drug Design*
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Protein Conformation
  • Proto-Oncogene Proteins c-met / chemistry
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzamides
  • Proto-Oncogene Proteins c-met