Novel hydroxybenzylamine-deoxyvasicinone hybrids as anticholinesterase therapeutics for Alzheimer's disease

Bioorg Med Chem. 2021 Sep 1;45:116311. doi: 10.1016/j.bmc.2021.116311. Epub 2021 Jul 14.

Abstract

A series of novel 2-hydroxybenzylamine-deoxyvasicinone hybrid analogs (8a-8n) have been synthesized and evaluated as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and as inhibitors of amyloid peptide (Aβ1-42) aggregation, for treatment of Alzheimer's disease (AD). These dual acting compounds exhibited good AChE inhibitory activities ranging from 0.34 to 6.35 µM. Analogs8g and 8n were found to be the most potent AChE inhibitors in the series with IC50values of 0.38 µM and 0.34 µM, respectively. All the analogs (8a-8n) exhibited weak BuChE inhibitory activities ranging from 14.60 to 21.65 µM. Analogs8g and 8n exhibited BuChE with IC50values of 15.38 µM and 14.60 µM, respectively, demonstrating that these analogs were greater than 40-fold more selective for inhibition of AChE over BuChE. Additionally, compounds8g and 8n were also found to be the best inhibitors of self-induced Aβ1-42 peptide aggregation with IC50values of 3.91 µM and 3.22 µM, respectively; 8g and 8n also inhibited AChE-induced Aβ1-42 peptide aggregation by 68.7% and 72.6%, respectively. Kinetic analysis and molecular docking studies indicate that analogs 8g and 8n bind to a new allosteric pocket (site B) on AChE. In addition, the observed inhibition of AChE-induced Aβ1-42 peptide aggregation by 8n is likely due to allosteric inhibition of the binding of this peptide at the CAS site on AChE. Overall, these results indicate that 8g and 8n are examples of dual-acting lead compounds for the development of highly effective anti-AD drugs.

Keywords: 2-Hydroxybenzylamine; Acetylcholinesterase inhibitors; Alzheimer’s disease; Aβ(1-42) peptide Aggregation; Deoxyvasicinone.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alkaloids / chemistry
  • Alkaloids / pharmacology*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Benzylamines / chemistry
  • Benzylamines / pharmacology*
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Electrophorus
  • Horses
  • Humans
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Protein Aggregates / drug effects
  • Structure-Activity Relationship

Substances

  • Alkaloids
  • Amyloid beta-Peptides
  • Benzylamines
  • Cholinesterase Inhibitors
  • Neuroprotective Agents
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • benzylamine
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • vasicinone