Phthalimide-Derived N-Benzylpyridinium Halides Targeting Cholinesterases: Synthesis and Bioactivity of New Potential Anti-Alzheimer's Disease Agents

Arch Pharm (Weinheim). 2016 Apr;349(4):293-301. doi: 10.1002/ardp.201500425. Epub 2016 Feb 22.

Abstract

In order to develop potent dual-binding cholinesterase inhibitors as potential drugs for the treatment of Alzheimer's disease, we designed and synthesized phthalimide-based acetylcholinesterase (AChE) inhibitors (7) containing a substituted N-benzylpyridinium residue. The in vitro anti-cholinesterase assay employing the target compounds against AChE and butyrylcholinesterase (BChE) revealed the 2-fluorobenzylpyridinium derivative 7d as the most potent compound against both enzymes, with IC50 values of 0.77 and 8.71 μM. The docking study of compound 7d into the active site of AChE showed the gorge-spanning binding mode, in which the compound spans the narrow hydrophobic gorge from the bottom to the rim.

Keywords: 1,3-Dioxoisoindoline; Acetylcholinesterase; Alzheimer's disease; Phthalimide; Pyridinium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Alzheimer Disease / drug therapy*
  • Animals
  • Butyrylcholinesterase / chemistry
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry*
  • Horses
  • Molecular Docking Simulation
  • Phthalimides / chemical synthesis
  • Phthalimides / chemistry*
  • Pyridinium Compounds / chemical synthesis
  • Pyridinium Compounds / chemistry*
  • Structure-Activity Relationship
  • Torpedo

Substances

  • Cholinesterase Inhibitors
  • Phthalimides
  • Pyridinium Compounds
  • Acetylcholinesterase
  • Butyrylcholinesterase