title: Multi-target strategy to address Alzheimer's disease: design, synthesis and biological evaluation of new tacrine-based dimers.
abstract: The multifactorial nature of Alzheimer's disease (AD) offers us a textbook example where parental compounds, mostly marketed, are modified with the aim of improving and/or conferring two or even more biological activities to contrast or less frequently revert the disease's symptoms. This is the case of tacrine and its dimeric derivative bis(7)-tacrine which, for instance, paved the way for the development of a broad collection of very interesting homo- and heterodimeric structures, conceived in light of the emerging multi-target approach for AD-related drug discovery. As a contribution to the topic, we report here the design, synthesis and biological evaluation of 12 compounds referable to bis(7)-tacrine. In addition to the cholinesterase activity, some of the selected compounds (7-9 and 12) were capable of inhibiting the non-enzymatic function of AChE and/or showed a remarkable activity against BACE1. Thus, the present study outlines a series of newly synthesized molecules, structurally related to bis(7)-tacrine, endowed with extended biological profile in agreement with the emerging multi-target paradigm.
authors.affiliation: Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Str 11, 44227 Dortmund, Germany.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rizzo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bisi
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancini
authors.forename: Federica
authors.initials: F
authors.lastname: Belluti
authors.forename: Silvia
authors.initials: S
authors.lastname: Gobbi
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Angela
authors.initials: A
authors.lastname: Rampa
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D019281:Dimerization; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013619:Tacrine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D013619:Tacrine