title: Naturally Inspired Molecules as Multifunctional Agents for Alzheimer's Disease Treatment.
abstract: Alzheimer's disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeutic strategies aimed at preventing Aβ generation and oxidative stress may represent an effective approach for AD treatment. A recent paradigm for the treatment of complex diseases such as AD suggests the employment of multifunctional compounds, single chemical entities capable of simultaneously modulating different targets involved in the pathology. In this paper, the "pharmacophores combination" strategy was applied, connecting the main scaffold of the BACE-1 ligand 1 to that of the chalcone 2, as metal chelating pharmacophore, to obtain a small library of compounds. Conjugate 5 emerged as the most interesting derivative, proving to inhibit BACE-1 with low-micromolar potency, and showing neuroprotective effects. In particular, 5 proved to be able to protect from metal-associated oxidative stress by hampering intracellular Cu(2+)-induced ROS formation without any direct neurotoxic effect.
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. angela.rampa@unibo.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Rampa
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso D'Augusto 237, 47921 Rimini, Italy. andrea.tarozzi@unibo.it.
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. francymancini@gmail.com.
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. letizia.pruccoli@studio.unibo.it.
authors.forename: Letizia
authors.initials: L
authors.lastname: Pruccoli
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. ritamaria.dimartino2@unibo.it.
authors.forename: Rita Maria Concetta
authors.initials: RM
authors.lastname: Di Martino
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. silvia.gobbi@unibo.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gobbi
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. alessandra.bisi@unibo.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bisi
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso D'Augusto 237, 47921 Rimini, Italy. angela.desimone2@unibo.it.
authors.forename: Angela
authors.initials: A
authors.lastname: De Simone
authors.affiliation: Department of Chemistry ''G. Ciamician'', Alma Mater Studiorum-University of Bologna, Via Selmi 2, 40126 Bologna, Italy. francesco.palomba3@unibo.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Palomba
authors.affiliation: Department of Chemistry ''G. Ciamician'', Alma Mater Studiorum-University of Bologna, Via Selmi 2, 40126 Bologna, Italy. nelsi.zaccheroni@unibo.it.
authors.forename: Nelsi
authors.initials: N
authors.lastname: Zaccheroni
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. federica.belluti@unibo.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Belluti
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry; D002599:Chalcone / Q000008:administration & dosage* / Q000737:chemistry; D002614:Chelating Agents / Q000008:administration & dosage / Q000737:chemistry; D004338:Drug Combinations; D006801:Humans; D007477:Ions / Q000737:chemistry; D008024:Ligands; D008670:Metals / Q000737:chemistry; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects; D066263:Protein Aggregation, Pathological / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D004338:Drug Combinations; D007477:Ions; D008024:Ligands; D008670:Metals; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D002599:Chalcone; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: AD; BACE-1; Reactive oxygen species; benzophenone; chalcone; metal chelation; natural products