Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta

Molecules. 2016 Mar 26;21(4):410. doi: 10.3390/molecules21040410.


Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer's disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention--compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM). Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE) (EeAChE IC50 = 0.76 μM, EqBuChE IC50 = 0.618 μM), and it inhibits amyloid beta aggregation (35.8% at 10 μM). Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB) was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer's agents.

Keywords: Alzheimer’s disease; PAMPA-BBB assay; cholinesterase inhibitors; molecular modelling; multi-target-directed ligands (MTDL); β-amyloid aggregation inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / therapeutic use*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / chemical synthesis
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / therapeutic use*
  • Binding Sites
  • Blood-Brain Barrier / drug effects
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / therapeutic use
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / therapeutic use*
  • Humans
  • Isoindoles / chemical synthesis
  • Isoindoles / chemistry
  • Isoindoles / therapeutic use
  • Ligands
  • Models, Molecular
  • Protein Aggregation, Pathological / drug therapy*
  • Protein Aggregation, Pathological / metabolism
  • Structure-Activity Relationship


  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Isoindol-1-one
  • Isoindoles
  • Ligands
  • Acetylcholinesterase
  • Butyrylcholinesterase