Design, Synthesis and Evaluation of 2-arylethenyl-N-methylquinolinium Derivatives as Effective Multifunctional Agents for Alzheimer's Disease Treatment

Eur J Med Chem. 2017 Apr 21;130:139-153. doi: 10.1016/j.ejmech.2017.02.042. Epub 2017 Feb 20.


A series of 2-arylethenyl-N-methylquinolinium derivatives were designed and synthesized based on our previous research of 2-arylethenylquinoline analogues as multifunctional agents for the treatment of Alzheimer's disease (AD) (Eur. J. Med. Chem. 2015, 89, 349-361). The results of in vitro biological activity evaluation, including β-amyloid (Aβ) aggregation inhibition, cholinesterase inhibition, and antioxidant activity, showed that introduction of N-methyl in quinoline ring significantly improved the anti-AD potential of compounds. The optimal compound, compound a12, dramatically attenuated the cell death of glutamate-induced HT22 cells by preventing the generation of ROS and increasing the level of GSH. Most importantly, intragastric administration of a12•HAc was well tolerated at doses up to 2000 mg/kg and could traverse blood-brain barrier.

Keywords: 2-arylethenyl-N-methylquinolinium derivatives; Alzheimer's disease; Aβ aggregation; Cholinesterase inhibition; Neuroprotection.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / drug effects
  • Antioxidants / chemistry
  • Antioxidants / pharmacology
  • Blood-Brain Barrier / metabolism
  • Cell Death / drug effects
  • Cell Line
  • Cholinesterase Inhibitors / chemistry
  • Drug Design
  • Glutathione / metabolism
  • Humans
  • Quinolines / chemistry*
  • Quinolines / pharmacology
  • Reactive Oxygen Species / metabolism


  • Amyloid beta-Peptides
  • Antioxidants
  • Cholinesterase Inhibitors
  • Quinolines
  • Reactive Oxygen Species
  • quinoline
  • Glutathione