title: Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents.
abstract: Tremendous efforts have been dedicated to the development of effective therapeutics against Alzheimer's disease, which represents the most common debilitating neurodegenerative disease. Multifunctional agents are molecules designed to have simultaneous effects on different pathological processes. Such compounds represent an emerging strategy for the development of effective treatments against Alzheimer's disease. Here, we report on the synthesis and biological evaluation of a series of nitroxoline-based analogs that were designed by merging the scaffold of 8-hydroxyquinoline with that of a known selective butyrylcholinesterase inhibitor that has promising anti-Alzheimer properties. Most strikingly, compound 8g inhibits self-induced aggregation of the amyloid beta peptide (Aβ1-42), inhibits with sub-micromolar potency butyrylcholinesterase (IC50=215 nM), and also selectively complexes Cu(2+). Our study thus designates this compound as a promising multifunctional agent for therapeutic treatment of Alzheimer's disease. The crystal structure of human butyrylcholinesterase in complex with compound 8g is also solved, which suggests ways to further optimize compounds featuring the 8-hydroxyquinoline scaffold.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Damijan
authors.initials: D
authors.lastname: Knez
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Boris
authors.initials: B
authors.lastname: Brus
authors.affiliation: Institut de Biologie Structurale (IBS), University Grenoble Alpes, F-38044 Grenoble, France; IBS, CNRS, F-38044 Grenoble, France; IBS, CEA, F-38044 Grenoble, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Coquelle
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Izidor
authors.initials: I
authors.lastname: Sosič
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Roman
authors.initials: R
authors.lastname: Šink
authors.affiliation: Institut de Recherche Biomédicale des Armées, 91223 Brétigny sur Orge, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Brazzolotto
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Janez
authors.initials: J
authors.lastname: Mravljak
authors.affiliation: Institut de Biologie Structurale (IBS), University Grenoble Alpes, F-38044 Grenoble, France; IBS, CNRS, F-38044 Grenoble, France; IBS, CEA, F-38044 Grenoble, France.
authors.forename: Jacques-Philippe
authors.initials: JP
authors.lastname: Colletier
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia. Electronic address: stanislav.gobec@ffa.uni-lj.si.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008670:Metals / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D009600:Nitroquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013056:Spectrophotometry, Ultraviolet
chemical_list: D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D008670:Metals; D009600:Nitroquinolines; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C005308:nitroxoline; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; Butyrylcholinesterase; Chelation; Multifunctional ligands; Nitroxoline