title: 2-Arylbenzofuran-based molecules as multipotent Alzheimer's disease modifying agents.
abstract: The complex etiology of Alzheimer's disease prompts scientists to develop multi-target strategies to combat causes and symptoms. In line with this modern paradigm and as a follow-up to our previous studies, we designed and synthesized a focused collection of new 2-arylbenzofurans and evaluated their biological properties towards specific targets involved in AD, namely human AChE and human BuChE, and Aβ fibril formation. Selected compounds were also tested for their ability to inhibit Aβ neurotoxicity in terms of neuronal viability loss, and to prevent Aβ peptide-binding to cell membrane and intracellular reactive oxygen species (ROS) formation. The different modifications introduced in the structure of our lead compound led to an increase in activity towards one or more of the selected targets: the anticholinesterase activity of some compounds was found to be significantly higher than previously obtained related molecules, and the compounds also proved to possess Aβ anti-aggregating properties and neuroprotective effects. The most interesting multi-target compounds were 18, and 1. Interestingly, 1 also showed good selectivity and moderate affinity for CB1 receptor, opening new perspectives in the field of research on AD, since cannabinoid ligands have been widely reported to have neuroprotective properties.
authors.affiliation: Department of Pharmaceutical Sciences, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rizzo
authors.forename: Andrea
authors.initials: A
authors.lastname: Tarozzi
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Gregory
authors.initials: G
authors.lastname: Da Costa
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bisi
authors.forename: Silvia
authors.initials: S
authors.lastname: Gobbi
authors.forename: Federica
authors.initials: F
authors.lastname: Belluti
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Marco
authors.initials: M
authors.lastname: Allarà
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Monti
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Patrizia
authors.initials: P
authors.lastname: Hrelia
authors.forename: Angela
authors.initials: A
authors.lastname: Rampa
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D001572:Benzofurans; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase