PUBLICATION
Synthesis and biological evaluation of novel pyrrolo[2,3-b]pyridine derivatives as potent GSK-3β inhibitors for treating Alzheimer's disease
- Authors
- Xun, Q.Q., Zhang, J., Li, Y.P., Li, Y., Ma, Y.Y., Chen, Z.B., Ding, L.P., Shi, X.L.
- ID
- ZDB-PUB-250113-2
- Date
- 2025
- Source
- European Journal of Medicinal Chemistry 285: 117236117236 (Journal)
- Registered Authors
- Keywords
- Alzheimer's disease, GSK-3β inhibitor, Neurite outgrowth, Tau hyperphosphorylation, pyrrolo[2,3-b]pyridine
- MeSH Terms
-
- Alzheimer Disease*/drug therapy
- Alzheimer Disease*/metabolism
- Animals
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Glycogen Synthase Kinase 3 beta*/antagonists & inhibitors
- Glycogen Synthase Kinase 3 beta*/metabolism
- Humans
- Mice
- Molecular Structure
- Protein Kinase Inhibitors/chemical synthesis
- Protein Kinase Inhibitors/chemistry
- Protein Kinase Inhibitors/pharmacology
- Pyridines*/chemical synthesis
- Pyridines*/chemistry
- Pyridines*/pharmacology
- Pyrroles*/chemical synthesis
- Pyrroles*/chemistry
- Pyrroles*/pharmacology
- Structure-Activity Relationship
- Zebrafish*
- PubMed
- 39798400 Full text @ Eur. J. Med. Chem.
Citation
Xun, Q.Q., Zhang, J., Li, Y.P., Li, Y., Ma, Y.Y., Chen, Z.B., Ding, L.P., Shi, X.L. (2025) Synthesis and biological evaluation of novel pyrrolo[2,3-b]pyridine derivatives as potent GSK-3β inhibitors for treating Alzheimer's disease. European Journal of Medicinal Chemistry. 285:117236117236.
Abstract
The development of potent glycogen synthase kinase-3β (GSK-3β) inhibitor has been increasingly recognized as the candidate treatment against the multifactorial pathogenic mechanism of Alzheimer's disease (AD). This study prepared various new pyrrolo[2,3-b]pyridine derivatives, evaluated the anti-AD activities and detected the security based on the structure-guided rational design. Our results indicated that many pyrrolo[2,3-b]pyridine derivatives had strong GSK-3β inhibitory activities, particularly compounds 41, 46 and 54, with the half maximal inhibitory concentrations (IC50) of 0.22, 0.26 and 0.24 nM, respectively, and each of them generally possessed GSK-3β selectivity over 24 structurally similar kinases. In addition, further targeting studies at the cellular level revealed that compound 41 increased GSK-3β phosphorylation at Ser9 site dose-dependently for inhibiting GSK-3β activity, therefore inhibiting the hyperphosphorylation of tau protein by decreasing the p-tau-Ser396 abundance. Moreover, 41 up-regulated β-catenin and neurogenesis-related markers (GAP43 and MAP-2), thereby promoting neurite outgrowth of neurons in SH-SY5Y cells. According to the in vitro cells assay, 41 showed the lower cytotoxicity to SH-SY5Y cells with a survival rate of over 70 % at the concentration of 100 μM. In vivo efficacy and acute toxicity experiments showed that, 41 effectively ameliorated the dyskinesia in AlCl3-induced zebrafish AD models and exhibited its low-toxicity nature in C57BL/6 mice. Overall, the pyrrolo[2,3-b]pyridine derivative 41 could serve as a promising GSK-3β inhibitor for treating AD.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping