期刊
ACS CHEMICAL NEUROSCIENCE
卷 7, 期 1, 页码 69-81出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.5b00224
关键词
Multifunctional agents; H3R antagonism; A beta aggregation inhibition; radical scavenge; metal ion chelation; Alzheimer's disease
资金
- National Natural Science Foundation of China [21172193]
- Zhejiang Provincial Natural Science Foundation of China [R2110297]
A series of novel 1-phenyl-3-hydroxy-4-pyridinone derivatives were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy through incorporation of 3-hydroxy-4-pyridinone moiety from deferiprone into the scaffold of H-3 receptor antagonists. Most of these new compounds displayed designed quadruple functions, H3 receptor antagonism, A beta aggregation inhibition, metal ion chelation, and radical scavenging. Especially, the most promising compound 5c displayed nanomolar IC50 values in H3 receptor antagonism with high selectivity, efficient capability to interrupt the formation of A beta(1-42) fibrils, good copper and iron chelating properties, and more potent 2,2'-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) radical cation (ABTS(center dot+)) scavenging activity than Trolox Further biological evaluation revealed that it did not show obvious cytotoxicity and hERG potassium channel inhibition at micromolar concentration. In addition, compound 5c demonstrated suitable pharmacokinetic properties and acceptable blood brain barrier (BBB) permeability in vivo. All these results indicate that compound 5c is a potential multifunctional candidate for AD therapy.
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