Turning Donepezil into a Multi-Target-Directed Ligand through a Merging Strategy.
Acetylcholinesterase
/ chemistry
Alzheimer Disease
/ drug therapy
Amyloid beta-Peptides
/ antagonists & inhibitors
Antioxidants
/ chemistry
Blood-Brain Barrier
/ diagnostic imaging
Cell Line, Tumor
Cell Survival
/ drug effects
Cholinesterase Inhibitors
/ chemistry
Donepezil
/ chemistry
Drug Design
Humans
Indans
/ chemistry
Ligands
Neuroprotective Agents
/ chemistry
Oxidative Stress
/ drug effects
Protein Aggregates
/ drug effects
Structure-Activity Relationship
Alzheimer's disease
drug design
medicinal chemistry
multi-target drug discovery
polypharmacology
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
08 01 2021
08 01 2021
Historique:
received:
04
07
2020
pubmed:
28
7
2020
medline:
18
9
2021
entrez:
28
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32716144
doi: 10.1002/cmdc.202000484
doi:
Substances chimiques
Amyloid beta-Peptides
0
Antioxidants
0
Cholinesterase Inhibitors
0
Indans
0
Ligands
0
Neuroprotective Agents
0
Protein Aggregates
0
Donepezil
8SSC91326P
indacrinone
B926Y9U4QN
Acetylcholinesterase
EC 3.1.1.7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
187-198Informations de copyright
© 2020 Wiley-VCH GmbH.
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