Synthesis and evaluation of heterobivalent tacrine derivatives as potential multi-functional anti-Alzheimer agents

Eur J Med Chem. 2011 Jun;46(6):2609-16. doi: 10.1016/j.ejmech.2011.03.058. Epub 2011 Apr 3.

Abstract

A new series of heterobivalent tacrine derivatives were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents for their inhibitory activity on cholinesterases, antioxidant activity and self-induced β-amyloid (Aβ) aggregation. All these synthesized compounds had potent inhibition activity on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) at nanomolar range. A Lineweaver-Burk plot and molecular modeling study showed that these compounds targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The compounds containing hydroxyl group showed potent peroxyl radical absorbance activity. In addition, compound 5j exhibited higher self-induced Aβ aggregation inhibitory activity than curcumin, which could become a multi-functional agent for further development for the treatment of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Antioxidants / metabolism
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tacrine / analogs & derivatives*
  • Tacrine / chemistry
  • Tacrine / pharmacology*

Substances

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