Click approach to the discovery of 1,2,3-triazolylsalicylamides as potent Aurora kinase inhibitors

Bioorg Med Chem. 2014 Sep 1;22(17):4855-66. doi: 10.1016/j.bmc.2014.06.047. Epub 2014 Jun 30.

Abstract

A series of 1,2,3-triazolylsalicylamide derivatives has been developed from the antiproliferative agent 7 and was evaluated for their Aurora kinase inhibitory activity. The novel 1,2,3-triazolylsalicylamide scaffold could be readily assembled by Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition, allowing rapid access to the structurally diverse analogues. The synthesized 1,2,3-triazolylsalicylamide derivatives revealed a significant Aurora kinase inhibitory activity. In particular, 8g inhibited Aurora A with IC50 values of 0.37μM. The critical role of phenolic -OH in the binding was confirmed by a molecular modeling study.

Keywords: 1,2,3-Triazole; Anticancer; Aurora kinase; Click chemistry; Library.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase A / antagonists & inhibitors*
  • Aurora Kinase A / metabolism
  • Aurora Kinase B / antagonists & inhibitors*
  • Aurora Kinase B / metabolism
  • Click Chemistry*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Salicylamides / chemical synthesis
  • Salicylamides / chemistry
  • Salicylamides / pharmacology*
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • Protein Kinase Inhibitors
  • Salicylamides
  • Triazoles
  • methyl 3-(5-(4-(3,5-dimethoxyphenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxybenzamido)benzoate
  • AURKA protein, human
  • Aurora Kinase A
  • Aurora Kinase B