title: Novel 8-Hydroxyquinoline Derivatives as Multitarget Compounds for the Treatment of Alzheimer's Disease.
abstract: We discovered a small series of hit compounds that show multitargeting activities against key targets in Alzheimer's disease (AD). The compounds were designed by combining the structural features of the anti-AD drug donepezil with clioquinol, which is able to chelate redox-active metals, thus decreasing metal-driven oxidative phenomena and β-amyloid (Aβ)-mediated neurotoxicity. The majority of the new hybrid compounds selectively target human butyrylcholinesterase at micromolar concentrations and effectively inhibit Aβ self-aggregation. In addition, compounds 5-chloro-7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (1 b), 7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (2 b), and 7-(((1-benzylpiperidin-4-yl)amino)methyl)-5-chloro-8-hydroxyquinoline (3 a) are able to chelate copper(II) and zinc(II) and exert antioxidant activity in vitro. Importantly, in the case of 2 b, the multitarget profile is accompanied by high predicted blood-brain barrier permeability, low cytotoxicity in T67 cells, and acceptable toxicity in HUVEC primary cells.
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6/Via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Prati
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6/Via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Christian
authors.identifier: 0000-0003-4387-5117
authors.initials: C
authors.lastname: Bergamini
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6/Via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Romana
authors.identifier: 0000-0002-8945-6826
authors.initials: R
authors.lastname: Fato
authors.affiliation: Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
authors.forename: Ondrej
authors.identifier: 0000-0001-6376-8701
authors.initials: O
authors.lastname: Soukup
authors.affiliation: Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
authors.forename: Jan
authors.identifier: 0000-0001-6977-7596
authors.initials: J
authors.lastname: Korabecny
authors.affiliation: Department for Quality Life Studies, Alma Mater Studiorum University of Bologna, Corso d'Augusto 237, 47921, Rimini, Italy.
authors.forename: Vincenza
authors.identifier: 0000-0003-4396-1904
authors.initials: V
authors.lastname: Andrisano
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6/Via Irnerio 48, 40126, Bologna, Italy. manuela.bartolini3@unibo.it.
authors.forename: Manuela
authors.identifier: 0000-0002-2890-3856
authors.initials: M
authors.lastname: Bartolini
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6/Via Irnerio 48, 40126, Bologna, Italy. marialaura.bolognesi@unibo.it.
authors.forename: Maria Laura
authors.identifier: 0000-0002-1289-5361
authors.initials: ML
authors.lastname: Bolognesi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000975:Antioxidants / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D007464:Clioquinol / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D003300:Copper / Q000737:chemistry; D000077265:Donepezil; D015195:Drug Design; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D015125:Oxyquinoline / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D010880:Piperidines / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D015125:Oxyquinoline; D003300:Copper; D007464:Clioquinol; D000077265:Donepezil; D002091:Butyrylcholinesterase; D015032:Zinc
keywords: Alzheimer′s disease; antioxidants; chelation; cholinesterases; inhibitors; β-amyloid