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.
Type de document :
Article dans une revue
Bioorganic & medicinal chemistry, Elsevier, 2017, 25 (2), pp.633-645. 〈10.1016/j.bmc.2016.11.032〉
Liste complète des métadonnées

http://hal.univ-grenoble-alpes.fr/hal-01465675
Contributeur : Frank Thomas <>
Soumis le : lundi 13 février 2017 - 08:45:47
Dernière modification le : lundi 19 février 2018 - 14:34:04

Identifiants

Collections

Citation

Urban Košak, Damijan Knez, Nicolas Coquelle, Boris Brus, Anja Pišlar, et al.. N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer's agents.. Bioorganic & medicinal chemistry, Elsevier, 2017, 25 (2), pp.633-645. 〈10.1016/j.bmc.2016.11.032〉. 〈hal-01465675〉

Partager

Métriques

Consultations de la notice

237