Design, synthesis, in vitro and in vivo evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer's disease.
J Enzyme Inhib Med Chem
; 35(1): 330-343, 2020 Dec.
Article
em En
| MEDLINE
| ID: mdl-31856607
ABSTRACT
Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer's disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, 15b and 15j showed submicromolar IC50 values (15b, eeAChE IC50 = 0.39 ± 0.11 µM; 15j, eqBChE IC50 = 0.16 ± 0.04 µM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that 15b and 15j act in a competitive manner. 15b and 15j showed neuroprotective effect against H2O2-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay in vitro. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of 15b and 15j was lower than tacrine. In summary, these data suggest 15b and 15j are promising multifunctional agents against AD.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Benzimidazóis
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Desenho de Fármacos
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Inibidores da Colinesterase
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Doença de Alzheimer
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Antioxidantes
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Enzyme Inhib Med Chem
Assunto da revista:
BIOQUIMICA
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QUIMICA
Ano de publicação:
2020
Tipo de documento:
Article