Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as dual inhibitors for cholinesterases and amyloid beta aggregation

Bioorg Med Chem. 2011 Jan 15;19(2):763-70. doi: 10.1016/j.bmc.2010.12.022. Epub 2010 Dec 13.

Abstract

A new series of tacrine-multialkoxybenzene hybrids (9a-9n) were designed, synthesized and evaluated as dual inhibitors of cholinesterases (ChEs) and self-induced β-amyloid (Aβ) aggregation. All the synthesized compounds had high acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity with IC₅₀ values at the nanomolar range, which were much better than tacrine alone. A Lineweaver-Burk plot and molecular modeling study showed that these hybrids targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, compounds 9a-9f with methylenedioxybenzene moiety showed higher self-induced Aβ aggregation inhibitory activity than a reference compound, curcumin. These compounds could be selected as multi-potent agents for further investigation to treat AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Acetylcholinesterase / metabolism
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Benzene / chemistry*
  • Binding Sites
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Computer Simulation
  • Drug Design
  • Kinetics
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism*
  • Tacrine / chemistry*

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Tacrine
  • Acetylcholinesterase
  • Benzene