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=215nM), 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.
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Bioorganic and Medicinal Chemistry, Elsevier, 2015, 23 (15), pp.4442-52
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http://hal.univ-grenoble-alpes.fr/hal-01199263
Contributeur : Frank Thomas <>
Soumis le : mardi 15 septembre 2015 - 11:04:11
Dernière modification le : lundi 19 février 2018 - 14:34:03

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  • HAL Id : hal-01199263, version 1
  • PUBMED : 26116179

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Damijan Knez, Boris Brus, Nicolas Coquelle, Izidor Sosič, Roman Šink, et al.. Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents.. Bioorganic and Medicinal Chemistry, Elsevier, 2015, 23 (15), pp.4442-52. 〈hal-01199263〉

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