Dual functional antioxidant and butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease: Design, synthesis and evaluation of novel melatonin-alkylbenzylamine hybrids.
Bioorg Med Chem
; 78: 117146, 2023 01 15.
Article
em En
| MEDLINE
| ID: mdl-36580744
ABSTRACT
Here, we have designed and synthesized a series of melatonin-alkylbenzylamine hybrids as multitarget agents for the treatment of Alzheimer's disease (AD). Most of them exhibited a potent multifunctional profile involving cholinesterase inhibition and antioxidant effects. Among these compounds, compound 5 was most the potent antioxidant (ORAC = 5.13) and also an excellent selective inhibitor of BuChE (huBuChE IC50 = 1.20 µM, huAChE IC50 = 177.49 µM, SI = 147.91). Moreover, kinetic study indicated compound 5 was a mixed-type inhibitor for huBuChE. Furthermore, it could induce expression of the Nrf2 as well as its downstream markers at the protein level in cells. More importantly, compound 5 display no acute toxicity in mice at doses up to 2500 mg/kg. And we found compound 5 could improve memory function of scopolamine-induced amnesia mice. These results highlighted compound 5 as a possible hit molecule for further investigation of new anti-AD drugs.
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Base de dados:
MEDLINE
Assunto principal:
Fármacos Neuroprotetores
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Doença de Alzheimer
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Melatonina
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article