Web of Science: 67 cites, Scopus: 79 cites, Google Scholar: cites,
Multi-Target Directed Donepezil-Like Ligands for Alzheimer's Disease
Unzeta López, Mercedes (Universitat Autònoma de Barcelona. Institut de Neurociències)
Esteban, Gerard (Trinity College Dublin. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute)
Bolea Tomás, Irene (Universitat Autònoma de Barcelona. Institut de Neurociències)
Fogel, Wieslawa A. (Medical University of Lodz. Department of Hormone Biochemistry)
Ramsay, Rona R. (University of St Andrews. Biomedical Sciences Research Complex)
Youdim, Moussa B. H. (Ruth and Bruce Rappaport Faculty of Medicine. Department of Pharmacology)
Tipton, Keith F. (Trinity College Dublin. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute)
Marco-Contelles, José (Spanish National Research Council. Institute of General Organic Chemistry)
Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular

Data: 2016
Resum: HIGHLIGHTS Alzheimer's disease (AD), the most common form of adult onset dementia, is an age-related neurodegenerative disorder characterized by progressive memory loss, decline in language skills, and other cognitive impairments. Although its etiology is not completely known, several factors including deficits of acetylcholine, β-amyloid deposits, τ-protein phosphorylation, oxidative stress, and neuroinflammation are considered to play significant roles in the pathophysiology of this disease. For a long time, AD patients have been treated with acetylcholinesterase inhibitors such as donepezil (Aricept®) but with limited therapeutic success. This might be due to the complex multifactorial nature of AD, a fact that has prompted the design of new Multi-Target-Directed Ligands (MTDL) based on the "one molecule, multiple targets" paradigm. Thus, in this context, different series of novel multifunctional molecules with antioxidant, anti-amyloid, anti-inflammatory, and metal-chelating properties able to interact with multiple enzymes of therapeutic interest in AD pathology including acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases A and B have been designed and assessed biologically. This review describes the multiple targets, the design rationale and an in-house MTDL library, bearing the N -benzylpiperidine motif present in donepezil, linked to different heterocyclic ring systems (indole, pyridine, or 8-hydroxyquinoline) with special emphasis on compound ASS234, an N -propargylindole derivative. The description of the in vitro biological properties of the compounds and discussion of the corresponding structure-activity-relationships allows us to highlight new issues for the identification of more efficient MTDL for use in AD therapy.
Nota: Número d'acord de subvenció MINECO/SAF2012-33304
Nota: Número d'acord de subvenció MINECO/SAF2015-65586-R
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès
Document: article ; recerca ; publishedVersion
Matèria: Multi-target-directed ligands ; Donepezil ; Oxidative stress ; Anti-β-amyloid aggregation ; Alzheimer's disease
Publicat a: Frontiers in Neuroscience, Vol. 10 (May 2016) , art. 205, ISSN 1662-453X

DOI: 10.3389/fnins.2016.00205
PMID: 27252617

24 p, 5.9 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Neurociències (INc)
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 Registre creat el 2018-02-07, darrera modificació el 2020-11-01

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