Design, synthesis and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives as selective c-Met inhibitors

Bioorg Med Chem. 2017 Feb 1;25(3):886-896. doi: 10.1016/j.bmc.2016.12.002. Epub 2016 Dec 12.

Abstract

Two novel series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives bearing 1H-imidazole-4-carboxamido or (E)-3-hydrosulfonylacrylamido motifs (16-31 and 32-42) were designed, synthesized and evaluated for their in vitro cytotoxic activity. Most of the compounds exhibited moderate to excellent potency against tested three cell lines, and fifteen compounds were further examined for their inhibitory activity against c-Met kinase. The most promising compound 16 (c-Met kinase [IC50]=1.1nM) demonstrated high selectivity and remarkable cytotoxicity against HT-29, MKN-45 and A549 cells with IC50 values of 0.08, 0.22 and 0.07μM, which were 3.1-, 1.4- and 2.1-fold more active than Foretinib. The preliminary structure-activity relationships as well as molecular docking disclosed that 1H-imidazole-4-carboxamido as a linker was of great importance for the antitumor activity.

Keywords: 6,7-Disubstituted-4-(2-fluorophenoxy)quinolines; Antitumor activity; Molecular docking; Synthesis; c-Met.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Survival / 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 / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Quinolines
  • Proto-Oncogene Proteins c-met