Multitargeted drugs discovery: balancing anti-amyloid and anticholinesterase capacity in a single chemical entity.

Abstract

Memoquin (1) is a lead compound multitargeted against Alzheimer's disease (AD). It is an AChE inhibitor, free-radical scavenger, and inhibitor of amyloid-β (Aβ) aggregation. A new series of 1 derivatives was designed and synthesized by linking its 2,5-diamino-benzoquinone core with motifs that are present in the structure of known amyloid binding agents like curcumin, the benzofuran derivative SKF64346, or the benzothiazole bearing compounds KHG21834 and BTA-1. The weaker AChE inhibitory potencies and the concomitant nearly equipotent anti-amyloid activities of the new compounds with respect to 1 resulted in a more balanced biological profile against both targets. Selected compounds turned out to be effective Aβ aggregation inhibitors in a cell-based assay. By properly combining two or more distinct pharmacological properties in a molecule, we can achieve greater effectiveness compared to single-targeted drugs for investigating AD.

• Authors: Maria Laura Bolognesi, Manuela Bartolini, Andrea Tarozzi, Fabiana Morroni, Federica Lizzi, Andrea Milelli, Anna Minarini, Michela Rosini, Patrizia Hrelia, Vincenza Andrisano, Carlo Melchiorre
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 9 Pg. 2655-8 (May 01 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21236667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Alkanes
• Amyloid
• Amyloid beta-Peptides
• Cholinesterase Inhibitors
• Enzyme Inhibitors
• Ethylamines
• memoquin

Topics

• Alkanes (chemistry, pharmacology)
• Alzheimer Disease (drug therapy)
• Amyloid (antagonists & inhibitors, genetics)
• Amyloid beta-Peptides (antagonists & inhibitors, genetics)
• Cells, Cultured
• Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Drug Delivery Systems
• Drug Discovery
• Enzyme Inhibitors (pharmacology)
• Ethylamines (chemistry, pharmacology)
• Humans
• Inhibitory Concentration 50
• Molecular Structure