title: From the dual function lead AP2238 to AP2469, a multi-target-directed ligand for the treatment of Alzheimer's disease.
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 Aβ 42 self-aggregation, Aβ 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 Aβ 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.
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna Corso d'Augusto 237, 47921, Rimini, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tarozzi
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna Via Belmeloro 6, 40126, Bologna, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna Via Belmeloro 6, 40126, Bologna, Italy ; ICIQ - Institute of Chemical Research of Catalonia Avenida Països Catalans 16, 43007, Tarragona, Spain.
authors.forename: Lorna
authors.initials: L
authors.lastname: Piazzi
authors.affiliation: Department of Chemistry "Giacomo Ciamician", Alma Mater Studiorum-University of Bologna Via S. Giacomo 11, 40126, Bologna, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Valgimigli
authors.affiliation: Department of Chemistry "Giacomo Ciamician", Alma Mater Studiorum-University of Bologna Via S. Giacomo 11, 40126, Bologna, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Amorati
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna Corso d'Augusto 237, 47921, Rimini, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Bolondi
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna Corso d'Augusto 237, 47921, Rimini, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Djemil
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna Via Belmeloro 6, 40126, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancini
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna Corso d'Augusto 237, 47921, Rimini, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna Via Belmeloro 6, 40126, Bologna, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Rampa
keywords: Alzheimer's disease; anti-inflammatory properties; catechol derivative; multi-target ligand; neuroprotective properties; β-amyloid peptide