Two novel Donepezil-Lipoic acid hybrids: synthesis, Anticholinesterase and antioxidant activities and theoretical studies

Alzheimer disease (AD) is a complex disease related to multiple pathogenic mechanisms. A strategy to develop effective drugs is based on the so-called multi-target directed ligands (MTDL) by using hybrid compounds. So, in the present study, we have designed and synthesized two hybrids, containing th...

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Detalhes bibliográficos
Autores: Terra, Bruna S., Silva, Pedro H. C. da, Tramarin, Anna, Franco, Lucas L., Cunha, Elaine F. F. da, Macedo Junior, Fernando, Ramalho, Teodorico C., Bartolini, Manuela, Bolognesi, Maria L., Fátima, Ângelo de
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:Brasil
Recursos:Universidade Federal de Lavras (UFLA)
Repositorio:Repositório Institucional da UFLA
Idioma:inglés
OAI Identifier:oai:repositorio.ufla.br:1/33372
Acesso em linha:https://repositorio.ufla.br/handle/1/33372
Access Level:acceso abierto
Palavra-chave:Donepezil-lipoic acid hybrids
Alzheimer disease
Multi-target directed ligands
Híbridos de ácido donepezil-lipóico
Doença de alzheimer
Ligandos dirigidos multi-alvo
Descrição
Resumo:Alzheimer disease (AD) is a complex disease related to multiple pathogenic mechanisms. A strategy to develop effective drugs is based on the so-called multi-target directed ligands (MTDL) by using hybrid compounds. So, in the present study, we have designed and synthesized two hybrids, containing the indanone-piperidine moiety of donepezil, a drug approved for the treatment of AD, and the lipoic acid scaffold, an antioxidant compound endowed with neuroprotective effects. One hybrid was synthesized in four steps with 42% global yield, and the other hybrid in six steps with 19% global yield. The latter hybrid displayed moderate inhibitory activity against human acetylcholinesterase (hAChE) and greater activity against human butyrylcholinesterases (hBuChE). The selectivity for hBuChE was further rationalized by theoretical study. Importantly, the second hybrid showed a good antioxidant activity, exhibiting better ability in scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals than lipoic acid.

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