Investigating 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole as scaffold of butyrylcholinesterase-selective inhibitors with additional neuroprotective activities for Alzheimer's disease

Eur J Med Chem. 2019 Sep 1:177:414-424. doi: 10.1016/j.ejmech.2019.05.062. Epub 2019 May 28.


Due to the role of butyrylcholinesterase (BChE) in acetylcholine hydrolysis in the late stages of the Alzheimer's disease (AD), inhibitors of butyrylcholinesterase (BChE) have been recently envisaged, besides acetylcholinesterase (AChE) inhibitors, as candidates for treating mild-to-moderate AD. Herein, synthesis and AChE/BChE inhibition activity of some twenty derivatives of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (HHAI) is reported. Most of the newly synthesized HHAI derivatives achieved the inhibition of both ChE isoforms with IC50s in the micromolar range, with a structure-dependent selectivity toward BChE. Apparently, molecular volume and lipophilicity do increase selectivity toward BChE, and indeed the N2-(4-phenylbutyl) HHAI derivative 15d, which behaves as a mixed-type inhibitor, resulted the most potent (IC50 0.17 μM) and selective (>100-fold) inhibitor toward either horse serum and human BChE. Moreover, 15d inhibited in vitro self-induced aggregation of neurotoxic amyloid-β (Aβ) peptide and displayed neuroprotective effects in neuroblastoma SH-SY5Y cell line, significantly recovering (P < 0.001) cell viability when impaired by Aβ1-42 and hydrogen peroxide insults. Overall, this study highlighted HHAI as useful and versatile scaffold for developing new small molecules targeting some enzymes and biochemical pathways involved in the pathogenesis of AD.

Keywords: Acetylcholinesterase; Alzheimer's disease; Amyloid-β aggregation; Azepino[4,3-b]indole; Butyrylcholinesterase; Neuroprotection.

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Azepines / chemical synthesis
  • Azepines / chemistry
  • Azepines / metabolism
  • Azepines / pharmacology*
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism
  • Catalytic Domain
  • Cell Line, Tumor
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Free Radical Scavengers / chemical synthesis
  • Free Radical Scavengers / chemistry
  • Free Radical Scavengers / metabolism
  • Free Radical Scavengers / pharmacology
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Molecular Docking Simulation
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology*
  • Peptide Fragments / metabolism
  • Protein Binding / drug effects
  • Protein Multimerization / drug effects
  • Structure-Activity Relationship


  • Amyloid beta-Peptides
  • Azepines
  • Cholinesterase Inhibitors
  • Free Radical Scavengers
  • Indoles
  • Neuroprotective Agents
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Butyrylcholinesterase