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Exploiting the lipoic acid structure in the search for novel multitarget ligands against Alzheimer's disease.

Abstract
Lipoic acid (LA) is a natural antioxidant. Its structure was previously combined with that of the acetylcholinesterase inhibitor tacrine to give lipocrine (1), a lead compound multitargeted against Alzheimer's disease (AD). Herein, we further explore LA as a privileged structure for developing multimodal compounds to investigate AD. First, we studied the effect of LA chirality by evaluating the cholinesterase profile of 1's enantiomers. Then, a new series of LA hybrids was designed and synthesized by combining racemic LA with motifs of other known anticholinesterase agents (rivastigmine and memoquin). This afforded 4, which represents a step forward in the search for balanced anticholinesterase and antioxidant capacities.
AuthorsMichela Rosini, Elena Simoni, Manuela Bartolini, Andrea Tarozzi, Riccardo Matera, Andrea Milelli, Patrizia Hrelia, Vincenza Andrisano, Maria Laura Bolognesi, Carlo Melchiorre
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 46 Issue 11 Pg. 5435-42 (Nov 2011) ISSN: 1768-3254 [Electronic] France
PMID21924801 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Amyloid beta-Peptides
  • Antioxidants
  • Cholinesterase Inhibitors
  • Ligands
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • Thioctic Acid
  • Acetylcholinesterase
  • Butyrylcholinesterase
Topics
  • Acetylcholinesterase (metabolism)
  • Alzheimer Disease (drug therapy)
  • Amyloid beta-Peptides (chemistry)
  • Antioxidants (chemical synthesis, chemistry, pharmacology, therapeutic use)
  • Butyrylcholinesterase (metabolism)
  • Cell Line
  • Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology, therapeutic use)
  • Drug Discovery (methods)
  • Humans
  • Ligands
  • Peptide Fragments (chemistry)
  • Protein Multimerization (drug effects)
  • Protein Structure, Secondary
  • Thioctic Acid (chemical synthesis, chemistry, pharmacology, therapeutic use)

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