Design, synthesis and biological evaluation of 2-acetyl-5-O-(amino-alkyl)phenol derivatives as multifunctional agents for the treatment of Alzheimer's disease.
Bioorg Med Chem Lett
; 27(22): 5046-5052, 2017 11 15.
Article
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| MEDLINE
| ID: mdl-29033233
ABSTRACT
A series of 2-acetyl-5-O-(amino-alkyl)phenol derivatives was designed, synthesized and evaluated as multi-function inhibitors for the treatment of Alzheimer's disease (AD). The results revealed that compound TM-3 indicated selective AChE inhibitory potency (eeAChE, IC50â¯=â¯0.69⯵M, selective index (SI)â¯=â¯32.7). Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-3 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. And TM-3 was also a highly selective MAO-B inhibitor (IC50â¯=â¯6.8⯵M). Moreover, TM-3 could act as antioxidant (ORAC value was 1.5eq) and neuroprotectant, as well as a selective metal chelating agent. More interestingly, compound TM-3 could cross the blood-brain barrier (BBB) in vitro and abided by Lipinski's rule of five. Therefore, compound TM-3, a promising multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against AD.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fenoles
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Piperazinas
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Benzofenonas
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Diseño de Fármacos
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Fármacos Neuroprotectores
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Enfermedad de Alzheimer
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Antioxidantes
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2017
Tipo del documento:
Article