title: N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer's agents.
abstract: In the brains of patients with Alzheimer's disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer's disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid β-peptide species.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Urban
authors.initials: U
authors.lastname: Košak
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Damijan
authors.initials: D
authors.lastname: Knez
authors.affiliation: Institut de Biologie Structurale, Univ. Grenoble Alpes, CEA, CNRS, 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: Boris
authors.initials: B
authors.lastname: Brus
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Anja
authors.initials: A
authors.lastname: Pišlar
authors.affiliation: Institut de Recherche Biomédicale des Armées, 91223 Brétigny-sur-Orge, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Nachon
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: Janko
authors.initials: J
authors.lastname: Kos
authors.affiliation: Institut de Biologie Structurale, Univ. Grenoble Alpes, CEA, CNRS, 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 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D008996:Monoamine Oxidase Inhibitors; D009281:Naphthalenes; D010446:Peptide Fragments; D010880:Piperidines; D013449:Sulfonamides; C075222:amyloid beta-protein (1-42); C000621777:naphthalene-2-carboxamide; C051353:naphthalenesulfonamide; D008995:Monoamine Oxidase; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; Butyrylcholinesterase inhibitors; MAO-B inhibitors; Multitarget-directed ligands