Discovery of novel 6-hydroxybenzothiazole urea derivatives as dual Dyrk1A/α-synuclein aggregation inhibitors with neuroprotective effects.
Cell Survival
/ drug effects
Dose-Response Relationship, Drug
Drug Discovery
HEK293 Cells
Humans
Molecular Structure
Neuroprotective Agents
/ chemical synthesis
Protein Aggregates
/ drug effects
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Protein-Tyrosine Kinases
/ antagonists & inhibitors
Structure-Activity Relationship
Thiazoles
/ chemical synthesis
Urea
/ analogs & derivatives
alpha-Synuclein
/ antagonists & inhibitors
Dyrk Kinases
Benzothiazoles
Dyrk1A inhibitors
Neuroprotective
Parkinson’s disease
α-synuclein aggregation
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 Jan 2022
05 Jan 2022
Historique:
received:
09
06
2021
revised:
04
10
2021
accepted:
06
10
2021
pubmed:
29
10
2021
medline:
27
1
2022
entrez:
28
10
2021
Statut:
ppublish
Résumé
A role of Dyrk1A in the progression of Down syndrome-related Alzheimer's disease (AD) is well supported. However, the involvement of Dyrk1A in the pathogenesis of Parkinson's disease (PD) was much less studied, and it is not clear whether it would be promising to test Dyrk1A inhibitors in relevant PD models. Herein, we modified our previously published 1-(6-hydroxybenzo[d]thiazol-2-yl)-3-phenylurea scaffold of Dyrk1A inhibitors to obtain a new series of analogues with higher selectivity for Dyrk1A on the one hand, but also with a novel, additional activity as inhibitors of α-synuclein (α-syn) aggregation, a major pathogenic hallmark of PD. The phenyl acetamide derivative b27 displayed the highest potency against Dyrk1A with an IC
Identifiants
pubmed: 34710745
pii: S0223-5234(21)00760-1
doi: 10.1016/j.ejmech.2021.113911
pii:
doi:
Substances chimiques
Neuroprotective Agents
0
Protein Aggregates
0
SNCA protein, human
0
Thiazoles
0
alpha-Synuclein
0
6-hydroxybenzothiazole
13599-84-3
Urea
8W8T17847W
Protein-Tyrosine Kinases
EC 2.7.10.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
113911Informations de copyright
Copyright © 2021 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.