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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

Texto completo
Autor(es):
Mantoani, Susimaire P. [1] ; Chierrito, Talita P. C. [1] ; Vilela, Adriana F. L. [2] ; Cardoso, Carmen L. [2] ; Martinez, Ana [3] ; Carvalho, Ivone [1]
Número total de Autores: 6
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, BR-14040903 Ribeirao Preto - Brazil
[2] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Quim, Grp Cromatog Bioafinidade & Prod Nat, BR-14040901 Ribeirao Preto - Brazil
[3] CSIC, Ctr Invest Biol, Madrid 28040 - Spain
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: Molecules; v. 21, n. 2 FEB 2016.
Citações Web of Science: 18
Resumo

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 -amyloid (A) protein, acting as a chaperone and increasing the number and neurotoxicity of A fibrils. It is known that AChE has two binding sites: the peripheral site, responsible for the interactions with A, 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. (AU)

Processo FAPESP: 13/50788-3 - Novos e potenciais agentes anti-Alzheimer: do planejamento aos estudos clínicos
Beneficiário:Ivone Carvalho
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 13/01710-1 - Ligantes enzimáticos: novos modelos de triagem
Beneficiário:Quezia Bezerra Cass
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 12/04054-5 - Síntese de potencial inibidor de acetilcolinesterase para tratamento da Doença de Alzheimer
Beneficiário:Talita Perez Cantuaria Chierrito
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 12/14114-5 - Planejamento, síntese e avaliação de inibidores duplos de acetilcolinesterase como potenciais candidatos a fármacos anti-Alzheimer
Beneficiário:Ivone Carvalho
Linha de fomento: Auxílio à Pesquisa - Regular