Highly selective butyrylcholinesterase inhibitors related to Amaryllidaceae alkaloids - Design, synthesis, and biological evaluation.
Alzheimer's disease
Amaryllidaceae alkaloids
Butyrylcholinesterase
Cholinesterase inhibitors
Crystallographic study
QSAR
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
05 Apr 2023
05 Apr 2023
Historique:
received:
13
02
2023
revised:
17
03
2023
accepted:
17
03
2023
medline:
14
4
2023
pubmed:
31
3
2023
entrez:
30
3
2023
Statut:
ppublish
Résumé
Butyrylcholinesterase (BChE) is one of the most frequently implicated enzymes in the advanced stage of Alzheimer's disease (AD). As part of our endeavors to develop new drug candidates for AD, we have focused on natural template structures, namely the Amaryllidaceae alkaloids carltonine A and B endowed with high BChE selectivity. Herein, we report the design, synthesis, and in vitro evaluation of 57 novel highly selective human BChE (hBChE) inhibitors. Most synthesized compounds showed hBChE inhibition potency ranging from micromolar to low nanomolar scale. Compounds that revealed BChE inhibition below 100 nM were selected for detailed biological investigation. The CNS-targeted profile of the presented compounds was confirmed theoretically by calculating the BBB score algorithm, these data were corroborated by determining the permeability in vitro using PAMPA-assay for the most active derivatives. The study highlighted compounds 87 (hBChE IC
Identifiants
pubmed: 36996715
pii: S0223-5234(23)00267-2
doi: 10.1016/j.ejmech.2023.115301
pii:
doi:
Substances chimiques
Butyrylcholinesterase
EC 3.1.1.8
Amaryllidaceae Alkaloids
0
Cholinesterase Inhibitors
0
Acetylcholinesterase
EC 3.1.1.7
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
115301Informations de copyright
Copyright © 2023 Elsevier Masson SAS. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.