دورية أكاديمية
The pyrazolo[4,3-c]pyrazole core as a novel and versatile scaffold for developing dual DYRK1A-CLK1 inhibitors targeting key processes of Alzheimer's disease pathology
| العنوان: | The pyrazolo[4,3-c]pyrazole core as a novel and versatile scaffold for developing dual DYRK1A-CLK1 inhibitors targeting key processes of Alzheimer's disease pathology |
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| المؤلفون: | Vaia-Argyro Bakalakou, Barbara Mavroidi, Amalia D. Kalampaliki, Béatrice Josselin, Stéphane Bach, Alexios-Leandros Skaltsounis, Panagiotis Marakos, Nicole Pouli, Maria Pelecanou, Vassilios Myrianthopoulos, Sandrine Ruchaud, Ioannis K. Kostakis |
| المصدر: | European Journal of Medicinal Chemistry Reports, Vol 12, Iss , Pp 100193- (2024) |
| بيانات النشر: | Elsevier, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Pharmacy and materia medica LCC:Other systems of medicine |
| مصطلحات موضوعية: | Kinase inhibitors, Metadynamics, pyrazolo[4,3-c]pyrazoles, Solvent mapping, Alzheimer's disease, Free energy perturbation, Pharmacy and materia medica, RS1-441, Other systems of medicine, RZ201-999 |
| الوصف: | In the current study, we designed, synthesized, and characterized a series of substituted pyrazolo[4,3-c]pyrazoles. These novel compounds were evaluated in vitro for their inhibitory activity over a panel of protein kinases to determine their potential therapeutic applications against Alzheimer's disease. To gain deeper insight into the binding interactions between the most potent analogues and their respective kinase targets, advanced molecular simulations were performed. In parallel, the ability of pyrazolo[4,3-c]pyrazoles to inhibit Aβ40 aggregation was assessed using biophysical techniques such as circular dichroism and Thioflavin T assays. Our results highlight the specific heterocycle as a highly promising and synthetically versatile scaffold for developing inhibitors of both AD-relevant kinases and amyloid-β aggregation. Although more effort is needed to assess the possibility of developing multi-target inhibitors, pyrazolo[4,3-c]pyrazole analogues demonstrated significant activities against their individual targets, indicating substantial capacity of the heterocyclic scaffold for further optimization toward both directions. Overall, our findings emphasize the potential of properly substituted pyrazolo[4,3-c]pyrazoles as multifunctional agents targeting key processes in Alzheimer's disease pathology. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2772-4174 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2772417424000657; https://doaj.org/toc/2772-4174 |
| DOI: | 10.1016/j.ejmcr.2024.100193 |
| URL الوصول: | https://doaj.org/article/eb0021815ee9431cabe5edd011eff369 |
| رقم الأكسشن: | edsdoj.b0021815ee9431cabe5edd011eff369 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 27724174 |
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| DOI: | 10.1016/j.ejmcr.2024.100193 |