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Turning Donepezil into a Multi-Target-Directed Ligand through a Merging Strategy.
- Source :
-
ChemMedChem [ChemMedChem] 2021 Jan 08; Vol. 16 (1), pp. 187-198. Date of Electronic Publication: 2020 Aug 31. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (© 2020 Wiley-VCH GmbH.)
- Subjects :
- Acetylcholinesterase chemistry
Acetylcholinesterase metabolism
Alzheimer Disease drug therapy
Amyloid beta-Peptides antagonists & inhibitors
Amyloid beta-Peptides metabolism
Antioxidants chemistry
Antioxidants metabolism
Antioxidants pharmacology
Blood-Brain Barrier diagnostic imaging
Blood-Brain Barrier metabolism
Cell Line, Tumor
Cell Survival drug effects
Cholinesterase Inhibitors chemistry
Cholinesterase Inhibitors metabolism
Cholinesterase Inhibitors pharmacology
Cholinesterase Inhibitors therapeutic use
Donepezil metabolism
Donepezil pharmacology
Donepezil therapeutic use
Drug Design
Humans
Indans chemistry
Neuroprotective Agents metabolism
Neuroprotective Agents pharmacology
Neuroprotective Agents therapeutic use
Oxidative Stress drug effects
Protein Aggregates drug effects
Structure-Activity Relationship
Donepezil chemistry
Ligands
Neuroprotective Agents chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 16
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 32716144
- Full Text :
- https://doi.org/10.1002/cmdc.202000484