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Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s Disease

التفاصيل البيبلوغرافية
العنوان: Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s Disease
المؤلفون: Ignazio Schino, Mariangela Cantore, Modesto de Candia, Cosimo D. Altomare, Catarina Maria, João Barros, Vasco Cachatra, Patrícia Calado, Karina Shimizu, Adilson A. Freitas, Maria C. Oliveira, Maria J. Ferreira, José N. C. Lopes, Nicola A. Colabufo, Amélia P. Rauter
المصدر: Pharmaceuticals, Vol 16, Iss 1, p 54 (2022)
بيانات النشر: MDPI AG, 2022.
سنة النشر: 2022
المجموعة: LCC:Medicine
LCC:Pharmacy and materia medica
مصطلحات موضوعية: cholinesterase inhibitors, copper chelators, purine nucleosides, Alzheimer’s disease, Medicine, Pharmacy and materia medica, RS1-441
الوصف: Alzheimer’s Disease (AD) is characterized by a progressive cholinergic neurotransmission imbalance, with a decrease of acetylcholinesterase (AChE) activity followed by a significant increase of butyrylcholinesterase (BChE) in the later AD stages. BChE activity is also crucial for the development of Aβ plaques, the main hallmarks of this pathology. Moreover, systemic copper dyshomeostasis alters neurotransmission leading to AD. In the search for structures targeting both events, a set of novel 6-benzamide purine nucleosides was synthesized, differing in glycone configuration and N7/N9 linkage to the purine. Their AChE/BChE inhibitory activity and metal ion chelating properties were evaluated. Selectivity for human BChE inhibition required N9-linked 6-deoxy-α-d-mannosylpurine structure, while all three tested β-d-derivatives appeared as non-selective inhibitors. The N9-linked l-nucleosides were cholinesterase inhibitors except the one embodying either the acetylated sugar or the N-benzyl-protected nucleobase. These findings highlight that sugar-enriched molecular entities can tune bioactivity and selectivity against cholinesterases. In addition, selective copper chelating properties over zinc, aluminum, and iron were found for the benzyl and acetyl-protected 6-deoxy-α-l-mannosyl N9-linked purine nucleosides. Computational studies highlight molecular conformations and the chelating molecular site. The first dual target compounds were disclosed with the perspective of generating drug candidates by improving water solubility.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1424-8247
Relation: https://www.mdpi.com/1424-8247/16/1/54; https://doaj.org/toc/1424-8247
DOI: 10.3390/ph16010054
URL الوصول: https://doaj.org/article/8753f9e020ec4afba27fb390b5193167
رقم الأكسشن: edsdoj.8753f9e020ec4afba27fb390b5193167
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:14248247
DOI:10.3390/ph16010054