Design and optimization of novel 4-(2-fluorophenoxy)quinoline derivatives bearing a hydrazone moiety as c-Met kinase inhibitors

Eur J Med Chem. 2014 Nov 24:87:508-18. doi: 10.1016/j.ejmech.2014.09.095. Epub 2014 Oct 2.

Abstract

A series of 4-(2-fluorophenoxy)quinoline derivatives containing an acylhydrazone moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and five cancer cell lines (A549, H460, HT-29, MKN-45, and U87MG). Most compounds showed weak to excellent antiproliferative activity. The most promising analog, 40 (c-Met IC50 = 1.86 nM), displayed 1.3-, 6.8-, 1.5-, 3.5-fold increase against HT-29, H460, A549 and U87MG cell lines, respectively, compared with Foretinib. An analysis of structure-activity relationships revealed that an acylhydrazone scaffold with an unsubstituted sp(2) hybridized carbon adjacent to the 4-CF3 phenyl ring is favorable for antitumor activity.

Keywords: Acylhydrazone; Quinoline derivatives; Synthesis; c-Met.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Drug Design
  • Humans
  • Hydrazones / analysis*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Quinolones / chemistry*
  • Quinolones / pharmacology*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Spectrometry, Mass, Electrospray Ionization
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Hydrazones
  • Protein Kinase Inhibitors
  • Quinolones
  • RON protein
  • Receptor Protein-Tyrosine Kinases