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Novel 8‐Hydroxyquinoline Derivatives as Multitarget Compounds for the Treatment of Alzheimer′s Disease
Author(s) -
Prati Federica,
Bergamini Christian,
Fato Romana,
Soukup Ondrej,
Korabecny Jan,
Andrisano Vincenza,
Bartolini Manuela,
Bolognesi Maria Laura
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600014
Subject(s) - chemistry , neurotoxicity , clioquinol , 8 hydroxyquinoline , cytotoxicity , antioxidant , chelation , blood–brain barrier , pharmacology , in vitro , drug , biochemistry , combinatorial chemistry , stereochemistry , toxicity , organic chemistry , biology , central nervous system , neuroscience
We discovered a small series of hit compounds that show multitargeting activities against key targets in Alzheimer′s disease (AD). The compounds were designed by combining the structural features of the anti‐AD drug donepezil with clioquinol, which is able to chelate redox‐active metals, thus decreasing metal‐driven oxidative phenomena and β‐amyloid (Aβ)‐mediated neurotoxicity. The majority of the new hybrid compounds selectively target human butyrylcholinesterase at micromolar concentrations and effectively inhibit Aβ self‐aggregation. In addition, compounds 5‐chloro‐7‐((4‐(2‐methoxybenzyl)piperazin‐1‐yl)methyl)‐8‐hydroxyquinoline ( 1 b ), 7‐((4‐(2‐methoxybenzyl)piperazin‐1‐yl)methyl)‐8‐hydroxyquinoline ( 2 b ), and 7‐(((1‐benzylpiperidin‐4‐yl)amino)methyl)‐5‐chloro‐8‐hydroxyquinoline ( 3 a ) are able to chelate copper(II) and zinc(II) and exert antioxidant activity in vitro. Importantly, in the case of 2 b , the multitarget profile is accompanied by high predicted blood–brain barrier permeability, low cytotoxicity in T67 cells, and acceptable toxicity in HUVEC primary cells.