Design, synthesis and biological evaluation of novel coumarin-N-benzyl pyridinium hybrids as multi-target agents for the treatment of Alzheimer's disease.
Eur J Med Chem
; 139: 48-59, 2017 Oct 20.
Article
em En
| MEDLINE
| ID: mdl-28797883
ABSTRACT
Combining N-benzyl pyridinium moiety and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activities were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for ChE and Aß (1-42) self-aggregation, and clearly selective inhibition to MAO-B over MAO-A. Of these compounds, compound 7f was the most potent inhibitor for hMAO-B, and it was also a good and balanced inhibitor to ChEs and hMAO-B (0.0373 µM for eeAChE; 2.32 µM for eqBuChE; 1.57 µM for hMAO-B). Molecular modeling and kinetic studies revealed that compound 7f was a mixed-type inhibitor, which bond simultaneously to CAS and PAS of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, compound 7f with no toxicity on PC12 neuroblastoma cells, showed good ability to inhibit Aß (1-42) self-aggregation and cross the BBB. Collectively, all these results suggested that compound 7f might be a promising multi-target lead candidate worthy of further pursuit.
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Base de dados:
MEDLINE
Assunto principal:
Compostos de Piridínio
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Desenho de Fármacos
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Inibidores da Colinesterase
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Cumarínicos
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Doença de Alzheimer
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Inibidores da Monoaminoxidase
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article