A new naphthalene derivative with anti-amyloidogenic activity as potential therapeutic agent for Alzheimer's disease

Bioorg Med Chem. 2020 Oct 15;28(20):115700. doi: 10.1016/j.bmc.2020.115700. Epub 2020 Aug 11.

Abstract

The aggregation of β-amyloid peptides is associated to neurodegeneration in Alzheimer's disease (AD) patients. Consequently, the inhibition of both oligomerization and fibrillation of β-amyloid peptides is considered a plausible therapeutic approach for AD. Herein, the synthesis of new naphthalene derivatives and their evaluation as anti-β-amyloidogenic agents are presented. Molecular dynamic simulations predicted the formation of thermodynamically stable complexes between the compounds, the Aβ1-42 peptide and fibrils. In human microglia cells, these compounds inhibited the aggregation of Aβ1-42 peptide. The lead compound 8 showed a high affinity to amyloid plaques in mice brain ex vivo assays and an adequate log Poct/PBS value. Compound 8 also improved the cognitive function and decreased hippocampal β-amyloid burden in the brain of 3xTg-AD female mice. Altogether, our results suggest that 8 could be a novel therapeutic agent for AD.

Keywords: 3xTg-AD; Alzheimer’s disease; Anti-amyloidogenic agent; Cognitive memory; Molecular dynamic simulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Dose-Response Relationship, Drug
  • Mice
  • Mice, Inbred C57BL
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Naphthalenes / chemical synthesis
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology*
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / metabolism
  • Protein Aggregates / drug effects*
  • Protein Aggregation, Pathological / drug therapy*
  • Protein Aggregation, Pathological / metabolism
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • Amyloid beta-Peptides
  • Naphthalenes
  • Neuroprotective Agents
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • naphthalene