Development and crystallography-aided SAR studies of multifunctional BuChE inhibitors and 5-HT6R antagonists with β-amyloid anti-aggregation properties

Eur J Med Chem. 2021 Dec 5:225:113792. doi: 10.1016/j.ejmech.2021.113792. Epub 2021 Aug 27.


The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and a challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins and processes involved in the development of the disease: BuChE, 5-HT6 receptors and β-amyloid aggregation. Structure-activity relationship analyses supported by crystallography and docking studies led to the identification of a fused-type multifunctional ligand 50, with remarkable and balanced potencies against BuChE (IC50 = 90 nM) and 5-HT6R (Ki = 4.8 nM), and inhibitory activity against Aβ aggregation (53% at 10 μM). In in vitro ADME-Tox and in vivo pharmacokinetic studies compound 50 showed good stability in the mouse liver microsomes, favourable safety profile and brain permeability with the brain to plasma ratio of 6.79 after p.o. administration in mice, thus being a promising candidate for in vivo pharmacology studies and a solid foundation for further research on effective anti-AD therapies.

Keywords: 5-HT(6) antagonists; Alzheimer's disease; BuChE inhibitors; Multifunctional ligands; β-amyloid.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Butyrylcholinesterase / metabolism*
  • Cell Survival / drug effects
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Development*
  • Electrophorus
  • Hep G2 Cells
  • Horses
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Protein Aggregates / drug effects
  • Receptors, Serotonin / metabolism*
  • Structure-Activity Relationship


  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Neuroprotective Agents
  • Protein Aggregates
  • Receptors, Serotonin
  • serotonin 6 receptor
  • Butyrylcholinesterase