Tacrine-hydroxamate derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation

Bioorg Chem. 2020 May:98:103721. doi: 10.1016/j.bioorg.2020.103721. Epub 2020 Mar 3.

Abstract

In order to develop multitarget-directed ligands as potential treatments for Alzheimer's disease, twenty-eight new tacrine-hydroxamate derivatives were designed, synthesized, and biologically evaluated. As expected, most of the compounds exhibited inhibitory activities against cholinesterases (ChEs) and histone deacetylase (HDACs). Among the tested compounds, A10 showed not only potent and selective inhibition on AChE at sub-nanomolar potency (AChEIC50 = 0.12 nM, BChEIC50 = 361.52 nM) but also potent inhibition on HDAC (IC50 = 0.23 nM). Moreover, A10 exhibited inhibitory activity on Aβ1-42 self-aggregation as well as disaggregation activity on pre-formed Aβ fibrils. Furthermore, A10 exhibited antioxidant activity and metal chelating properties. Further mechanistic studies demonstrated that A10 is a pan-inhibitor of HDACs and a mixed-type inhibitor for AChE. It shown that A10 is a BBB penetrant by online prediction. Taken together, the results indicate that A10 can serve as a lead compound to develop promising candidate analogs as AD therapeutics.

Keywords: Alzheimer's disease; Antioxidant; Cholinesterase inhibitor; Metal chelator; Multitarget-directed ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Electrophorus
  • HeLa Cells
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism
  • Horses
  • Humans
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology*
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Protein Aggregates / drug effects
  • Structure-Activity Relationship
  • Tacrine / chemistry
  • Tacrine / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Antioxidants
  • Cholinesterase Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Ligands
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • Tacrine
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Histone Deacetylases