Clicked tacrine conjugates as acetylcholinesterase and β-amyloid directed compounds

Org Biomol Chem. 2011 Feb 21;9(4):1140-7. doi: 10.1039/c0ob00393j. Epub 2010 Dec 10.

Abstract

The multifaceted nature of Alzheimer's disease (AD) has led to the development of multi-targeted compounds based on the classical AD drug, tacrine, first known to inhibit the acetylcholine-degrading enzyme acetylcholinesterase (AChE). In the present work, we explore the potentiality of multimers of tacrine in this field. The synthesis using the so-called "click chemistry" and the in vitro study of the conjugates are described. Two or four copies of the tacrine molecule are "clicked" on a constrained cyclopeptide template proven to be a convenient tool for multimeric presentation. The multimers significantly inhibit self-induced amyloid fibril formation from Aβ(40) at low inhibitor to Aβ molar ratios at which the tacrine monomer is fully inactive (Thioflavin T assays and AFM observation). Moreover, they have the capacity to bind to Aβ(40) fibrils (SPR assays) while retaining the AChE inhibitory activity of the parent tacrine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / ultrastructure
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / pharmacology
  • Inhibitory Concentration 50
  • Microscopy, Atomic Force
  • Molecular Structure
  • Tacrine / chemistry*

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Tacrine
  • Acetylcholinesterase