Design, synthesis and biological evaluation of LX2343 derivatives as neuroprotective agents for the treatment of Alzheimer's disease

Eur J Med Chem. 2018 Feb 10:145:622-633. doi: 10.1016/j.ejmech.2017.12.080. Epub 2018 Jan 2.

Abstract

A series of LX2343 derivatives were designed, synthesized and evaluated as neuroprotective agents for Alzheimer's disease (AD) in vitro. Most of the compounds displayed potent neuroprotective activities. Especially for compound A6, exhibited a remarkable EC50 value of 0.22 μM. Further investigation demonstrated that compound A6 can significantly reduce Aβ production and increase Aβ clearance, and alleviate Tau hyperphosphorylation. Most importantly, compound A6 could ameliorate learning and memory impairments in APP/PS1 transgenic mice. The present study evidently showed that compound A6 is a potent neuroprotective agent and might serve as a promising lead candidate for the treatment of Alzheimer's disease.

Keywords: Alzheimer's disease; LX2343 derivatives; Neuroprotective agents; Structural modifications; Structure-activity relationships.

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HEK293 Cells
  • Humans
  • Maze Learning / drug effects
  • Memory Disorders / drug therapy
  • Mice
  • Mice, Transgenic
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Acetamides
  • Amyloid beta-Peptides
  • LX2343
  • Neuroprotective Agents
  • Sulfonamides