Knez_2015_Bioorg.Med.Chem_23_4442

Reference

Title : Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents - Knez_2015_Bioorg.Med.Chem_23_4442
Author(s) : Knez D , Brus B , Coquelle N , Sosic I , Sink R , Brazzolotto X , Mravljak J , Colletier JP , Gobec S
Ref : Bioorganic & Medicinal Chemistry , 23 :4442 , 2015
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 (Abeta1-42), 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.
ESTHER : Knez_2015_Bioorg.Med.Chem_23_4442
PubMedSearch : Knez_2015_Bioorg.Med.Chem_23_4442
PubMedID: 26116179
Gene_locus related to this paper: human-BCHE

Related information

Gene_locus related to this paper: human-BCHE

Citations formats

Knez D, Brus B, Coquelle N, Sosic I, Sink R, Brazzolotto X, Mravljak J, Colletier JP, Gobec S (2015)
Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents
Bioorganic & Medicinal Chemistry 23 :4442

Knez D, Brus B, Coquelle N, Sosic I, Sink R, Brazzolotto X, Mravljak J, Colletier JP, Gobec S (2015)
Bioorganic & Medicinal Chemistry 23 :4442