Design and synthesis of novel benzo[d]oxazol-2(3H)-one derivatives bearing 7-substituted-4-enthoxyquinoline moieties as c-Met kinase inhibitors

Eur J Med Chem. 2016 Jun 10:115:191-200. doi: 10.1016/j.ejmech.2016.03.027. Epub 2016 Mar 12.

Abstract

Analysis of the results of studies of docking 1 and 7a with c-Met kinase led to the identification of benzo[d]oxazol-2(3H)-one-quinolone derivatives as potential inhibitors of this enzyme. A molecular hybrid strategy, using a 4-ethoxy-7-substituted-quinoline core and a benzo[d]oxazol-2(3H)-one scaffold, was employed to design members of this family for study as inhibitors of the kinase and proliferation of EBC-1 cells. Most of the substances were found to display good to excellent c-Met kinase inhibitory activities. The results of a structure-activity relationship (SAR) study led to the discovery of benzo[d]oxazol-2(3H)-one-quinolone 13, which has IC50 values of 1 nM against c-Met kinase and 5 nM against proliferation of the EBC-1 cell line.

Keywords: Anti-cancer; Benzo[d]oxazol-2(3H)-one-quinolone; Molecular hybridization; c-Met.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoxazoles / chemical synthesis
  • Benzoxazoles / chemistry
  • Benzoxazoles / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / metabolism
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Benzoxazoles
  • Protein Kinase Inhibitors
  • Quinolines
  • benzo(d)oxazol-2(3H)-one
  • MET protein, human
  • Proto-Oncogene Proteins c-met