Diversification of edaravone via palladium-catalyzed hydrazine cross-coupling: Applications against protein misfolding and oligomerization of beta-amyloid

Bioorg Med Chem Lett. 2016 Jan 1;26(1):100-4. doi: 10.1016/j.bmcl.2015.11.022. Epub 2015 Nov 10.

Abstract

N-Aryl derivatives of edaravone were identified as potentially effective small molecule inhibitors of tau and beta-amyloid aggregation in the context of developing disease-modifying therapeutics for Alzheimer's disease (AD). Palladium-catalyzed hydrazine monoarylation protocols were then employed as an expedient means of preparing a focused library of 21 edaravone derivatives featuring varied N-aryl substitution, thereby enabling structure-activity relationship (SAR) studies. On the basis of data obtained from two functional biochemical assays examining the effect of edaravone derivatives on both fibril and oligomer formation, it was determined that derivatives featuring an N-biaryl motif were four-fold more potent than edaravone.

Keywords: Alzheimer’s disease; Beta-amyloid; Hydrazine; Palladium-catalyzed aminations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism*
  • Antipyrine / analogs & derivatives*
  • Antipyrine / chemical synthesis
  • Antipyrine / chemistry
  • Antipyrine / pharmacology
  • Catalysis
  • Dose-Response Relationship, Drug
  • Edaravone
  • Hydrazines / chemistry*
  • Molecular Structure
  • Organometallic Compounds / chemistry
  • Palladium / chemistry*
  • Protein Folding / drug effects*
  • Protein Multimerization / drug effects*
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Hydrazines
  • Organometallic Compounds
  • hydrazine
  • Palladium
  • Edaravone
  • Antipyrine