Synthesis, biological evaluation and 3D-QSAR studies of novel 4,5-dihydro-1H-pyrazole niacinamide derivatives as BRAF inhibitors

Bioorg Med Chem. 2012 Jun 15;20(12):3746-55. doi: 10.1016/j.bmc.2012.04.047. Epub 2012 Apr 28.

Abstract

A series of novel 4,5-dihydropyrazole derivatives containing niacinamide moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Results of the bioassays against BRAF(V600E) and WM266.4 human melanoma cell line showed several compounds to be endowed potent activities with IC(50) and GI(50) value in low micromolar range, among which compound 27e, (5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)6-methylpyridin-3-yl methanone (IC(50)=0.20 μM, GI(50)=0.89 μM) was bearing the best bioactivity comparable with the positive control Sorafenib. Docking simulation was performed to determine the probable binding model and 3D-QSAR model was built to provide more pharmacophore understanding that could use to design new agents with more potent BRAF(V600E) inhibitory activity.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Drug Design
  • Humans
  • Mice
  • Models, Molecular
  • Niacinamide / chemistry
  • Niacinamide / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Quantitative Structure-Activity Relationship*
  • Rats
  • Tumor Cells, Cultured

Substances

  • Protein Kinase Inhibitors
  • Niacinamide
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf