Turning Donepezil into a Multi-Target-Directed Ligand through a Merging Strategy
Language English Country Germany Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- Alzheimer's disease, drug design, medicinal chemistry, multi-target drug discovery, polypharmacology,
- MeSH
- Acetylcholinesterase chemistry metabolism MeSH
- Alzheimer Disease drug therapy MeSH
- Amyloid beta-Peptides antagonists & inhibitors metabolism MeSH
- Antioxidants chemistry metabolism pharmacology MeSH
- Cholinesterase Inhibitors chemistry metabolism pharmacology therapeutic use MeSH
- Donepezil chemistry metabolism pharmacology therapeutic use MeSH
- Blood-Brain Barrier diagnostic imaging metabolism MeSH
- Indans chemistry MeSH
- Humans MeSH
- Ligands * MeSH
- Cell Line, Tumor MeSH
- Neuroprotective Agents chemistry metabolism pharmacology therapeutic use MeSH
- Oxidative Stress drug effects MeSH
- Protein Aggregates drug effects MeSH
- Drug Design MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Amyloid beta-Peptides MeSH
- Antioxidants MeSH
- Cholinesterase Inhibitors MeSH
- Donepezil MeSH
- indacrinone MeSH Browser
- Indans MeSH
- Ligands * MeSH
- Neuroprotective Agents MeSH
- Protein Aggregates MeSH
Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the "physicochemical challenge" typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.
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https://www.euro.who.int/en/healthtopics/noncommunicabl e-diseases/mental-health/areas-of-work/dementia.
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