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Molecules 2016, 21(2), 193; doi:10.3390/molecules21020193

Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors

School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-903, Brazil
Departamento de Química, Grupo de Cromatografia de Bioafinidade e Produtos Naturais, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto (FFCLRP), Universidade de São Paulo, Ribeirão Preto 14040-901, Brazil
Centro de Investigaciones Biológicas (CIB-CSIC), Madrid 28040, Spain
Authors to whom correspondence should be addressed.
Academic Editors: Michael Decker and Diego Muñoz-Torrero
Received: 10 December 2015 / Revised: 30 January 2016 / Accepted: 2 February 2016 / Published: 5 February 2016
(This article belongs to the Special Issue Molecules against Alzheimer)
View Full-Text   |   Download PDF [1090 KB, uploaded 5 February 2016]   |  


Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE) in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with the β-amyloid (Aβ) protein, acting as a chaperone and increasing the number and neurotoxicity of Aβ fibrils. It is known that AChE has two binding sites: the peripheral site, responsible for the interactions with Aβ, and the catalytic site, related with acetylcholine hydrolysis. In this work, we reported the synthesis and biological evaluation of a library of new tacrine-donepezil hybrids, as a potential dual binding site AChE inhibitor, containing a triazole-quinoline system. The synthesis of hybrids was performed in four steps using the click chemistry strategy. These compounds were evaluated as hAChE and hBChE inhibitors, and some derivatives showed IC50 values in the micro-molar range and were remarkably selective towards hAChE. Kinetic assays and molecular modeling studies confirm that these compounds block both catalytic and peripheral AChE sites. These results are quite interesting since the triazole-quinoline system is a new structural scaffold for AChE inhibitors. Furthermore, the synthetic approach is very efficient for the preparation of target compounds, allowing a further fruitful new chemical library optimization. View Full-Text
Keywords: Alzheimer’s disease; acetylcholinesterase; selective dual binding site inhibitors; click chemistry; triazole-quinoline derivatives Alzheimer’s disease; acetylcholinesterase; selective dual binding site inhibitors; click chemistry; triazole-quinoline derivatives

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Mantoani, S.P.; Chierrito, T.P.C.; Vilela, A.F.L.; Cardoso, C.L.; Martínez, A.; Carvalho, I. Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors. Molecules 2016, 21, 193.

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