Novel 8-Hydroxyquinoline Derivatives as Multitarget Compounds for the Treatment of Alzheimer's Disease
Language English Country Germany Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- Alzheimer′s disease, antioxidants, chelation, cholinesterases, inhibitors, β-amyloid,
- MeSH
- Alzheimer Disease drug therapy MeSH
- Amyloid beta-Peptides antagonists & inhibitors metabolism MeSH
- Antioxidants chemistry therapeutic use toxicity MeSH
- Butyrylcholinesterase chemistry metabolism MeSH
- Chelating Agents chemistry MeSH
- Cholinesterase Inhibitors chemistry therapeutic use toxicity MeSH
- Donepezil MeSH
- Human Umbilical Vein Endothelial Cells MeSH
- Blood-Brain Barrier metabolism MeSH
- Indans chemistry therapeutic use toxicity MeSH
- Clioquinol chemistry therapeutic use toxicity MeSH
- Humans MeSH
- Copper chemistry MeSH
- Cell Line, Tumor MeSH
- Oxyquinoline chemistry therapeutic use toxicity MeSH
- Piperidines chemistry therapeutic use toxicity MeSH
- Drug Design MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Zinc chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Amyloid beta-Peptides MeSH
- Antioxidants MeSH
- Butyrylcholinesterase MeSH
- Chelating Agents MeSH
- Cholinesterase Inhibitors MeSH
- Donepezil MeSH
- Indans MeSH
- Clioquinol MeSH
- Copper MeSH
- Oxyquinoline MeSH
- Piperidines MeSH
- Zinc MeSH
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.
References provided by Crossref.org
Profiling donepezil template into multipotent hybrids with antioxidant properties
