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...
| Autores: | , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2018 |
| País: | Brasil |
| Institución: | Universidade Federal de Minas Gerais (UFMG) |
| Repositorio: | Repositório Institucional da UFMG |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.ufmg.br:1843/69757 |
| Acceso en línea: | http://dx.doi.org/10.21577/0103-5053.20170196 http://hdl.handle.net/1843/69757 https://orcid.org/0000-0002-9608-1559 https://orcid.org/0000-0003-2344-5590 https://orcid.org/0000-0002-5196-9845 https://orcid.org/0000-0002-3845-3801 https://orcid.org/0000-0002-4230-1309 https://orcid.org/0000-0002-7324-1353 https://orcid.org/0000-0002-2890-3856 https://orcid.org/0000-0002-1289-5361 |
| Access Level: | acceso abierto |
| Palabra clave: | Donepezil-lipoic acid hybrids Alzheimer disease Multi-target directed ligands Antioxidantes Alzheimer, Doença de Inibidores da colinesterase |
| Sumario: | 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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