Novel 8-hydroxyquinoline derivatives targeting ß-amyloid aggregation, metal chelation and oxidative stress against Alzheimer's disease.
Bioorg Med Chem
; 26(12): 3191-3201, 2018 07 23.
Article
em En
| MEDLINE
| ID: mdl-29729985
ABSTRACT
A series of multitargeted 8-hydroxyquinoline derivatives were designed and synthesized for the treatment of Alzheimer's disease (AD). In vitro studies indicated that most of the prepared compounds exhibited significant inhibitory effects against self-induced Aß1-42 aggregation and potential antioxidant properties especially compound 5b (IC50â¯=â¯5.64⯵M for self-induced Aß aggregation; the oxygen radical absorbance capacity using fluorescein (ORAC-FL) value is 2.63 Trolox equivalents). Notably, 5b can chelate biometals and inhibit Cu2+/Zn2+-induced Aß1-42 aggregation. The cell assays showed that 5b had excellent protective effects against oxidative toxin H2O2 and presented low neurotoxicity in PC12 cells. Furthermore, 5b could penetrate the blood-brain barrier (BBB) in vitro and did not show any acute toxicity in mice at doses up to 2000â¯mg/kg in vivo. Our findings provide a rationale for the potential application of compound 5b as a lead compound in AD therapy.
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MEDLINE
Assunto principal:
Quelantes
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Peptídeos beta-Amiloides
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Oxiquinolina
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Estresse Oxidativo
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Metais
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article