Design, synthesis and biological evaluation of novel copper-chelating acetylcholinesterase inhibitors with pyridine and N-benzylpiperidine fragments

Bioorg Chem. 2019 Dec:93:103322. doi: 10.1016/j.bioorg.2019.103322. Epub 2019 Sep 26.

Abstract

Cholinergic depletion is the direct cause of disability and dementia among AD patients. AChE is a classical and key target of cholinergic disorders. Some new inhibitors of AChE combining pyridine, acylhydrazone and N-benzylpiperidine fragments were developed in this work. The hit structure was optimized to yield the compound 21 with an IC50 value of 6.62 nM against AChE, while almost no inhibitory effect against BChE. ADMET predictions and PAMPA permeability evaluation showed good drug-like property. The higher activity with an intermediate alkyl chain substitution indicates a new binding mode of inhibitor with AChE. This finding provides new insights into the binding mechanism and is helpful for discovery of novel high-activity AChE inhibitors.

Keywords: Acetylcholinesterase; Copper-chelating; Dementia; Drug design; N-Benzylpiperidine; N-acylhydrazone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / drug effects*
  • Blood-Brain Barrier
  • Chelating Agents / chemical synthesis
  • Chelating Agents / chemistry*
  • Chelating Agents / pharmacology*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / pharmacology*
  • Copper / chemistry*
  • Drug Design*
  • Humans
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Piperidines / chemistry*
  • Pyridines / chemistry*
  • Structure-Activity Relationship

Substances

  • Chelating Agents
  • Cholinesterase Inhibitors
  • Piperidines
  • Pyridines
  • Copper
  • 1-benzylpiperidine
  • Acetylcholinesterase
  • pyridine