Open AccessFrom the dual function lead AP2238 to AP2469, a multi‐target‐directed ligand for the treatment of Alzheimer's disease
Author(s) -
Tarozzi Andrea,
Bartolini Manuela,
Piazzi Lorna,
Valgimigli Luca,
Amorati Riccardo,
Bolondi Cecilia,
Djemil Alice,
Mancini Francesca,
Andrisano Vincenza,
Rampa Angela
Publication year - 2014
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.23
Subject(s) - lead (geology) , disease , dual (grammatical number) , medicine , function (biology) , neuroscience , physical medicine and rehabilitation , psychology , biology , art , paleontology , literature , evolutionary biology
Abstract The development of drugs with different pharmacological properties appears to be an innovative therapeutic approach for Alzheimer's disease. In this article, we describe a simple structural modification of AP2238, a first dual function lead, in particular the introduction of the catechol moiety performed in order to search for multi‐target ligands. The new compound AP2469 retains anti‐acetylcholinesterase ( AChE ) and beta‐site amyloid precursor protein cleaving enzyme ( BACE )1 activities compared to the reference, and is also able to inhibit A β 42 self‐aggregation, A β 42 oligomer‐binding to cell membrane and subsequently reactive oxygen species formation in both neuronal and microglial cells. The ability of AP2469 to interfere with A β 42 oligomer‐binding to neuron and microglial cell membrane gives this molecule both neuroprotective and anti‐inflammatory properties. These findings, together with its strong chain‐breaking antioxidant performance, make AP2469 a potential drug able to modify the course of the disease.