Synthesis and evaluation of arylquinones as BACE1 inhibitors, β-amyloid peptide aggregation inhibitors, and destabilizers of preformed β-amyloid fibrils

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2183-7. doi: 10.1016/j.bmcl.2011.03.023. Epub 2011 Mar 13.

Abstract

BACE1 activity, inhibition of Aβ aggregation, and disaggregation of preformed Aβ fibrils constitute the three major targets in the development of small-molecule lipophilic new drugs for the treatment of Alzheimer's disease (AD). Quinones are widely distributed among natural products and possess relevant and varied biological activities including antitumor and antibiotic, inhibition of HIV-1 reverse transcriptase, antidiabetic, or COX-inhibition, among others. We report herein the interaction of several arylquinones and their derivatives with the amyloidogenic pathway of the amyloid precursor protein processing. Our studies put forward that these compounds are promising candidates in the development of new drugs which are effective simultaneously towards the three major targets of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Amyloid / chemistry*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Quinones / chemical synthesis
  • Quinones / chemistry*
  • Quinones / therapeutic use

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Quinones
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human