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Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3β for the Treatment of Alzheimer's Disease.


ABSTRACT: The pathogenesis of Alzheimer's disease (AD) is very complex, and there are many hypotheses. Therefore, the development of a multi-target-directed-ligand may be an effective therapeutic strategy. Our previous study showed that notopterol (a natural product from Notopterygium) is a dual BACE1/GSK3β inhibitor. In this study, we designed and synthesized 48 notopterol derivatives with furacoumarin as a scaffold in order to enhance their balanced AChE/BACE1/GSK3β inhibitory activity. Fortunately, 1c showed effective inhibitory activity against AChE (58.7% at 1.0 μM), BACE1 (48.3% at 20 μM), and GSK3β (40.3% at 10 μM). Furthermore, 1c showed good blood-brain barrier penetrability, suitable bioavailability, and oral safety. More importantly, 1c could ameliorate the impaired learning and memory in Aβ-induced AD mice. In conclusion, we reported the triple inhibitor of AChE/BACE1/GSK3β lead compounds based on a furocoumarin scaffold of notopterol for the first time, which provides a potential new strategy for the treatment of AD.

SUBMITTER: Wang N 

PROVIDER: S-EPMC9476211 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3β for the Treatment of Alzheimer's Disease.

Wang Nan N   Liu Wenjie W   Zhou Lijun L   Liu Wenwu W   Liang Xu X   Liu Xin X   Xu Zihua Z   Zhong Tianming T   Wu Qiong Q   Jiao Xinming X   Chen Jiangxia J   Ning Xinyue X   Jiang Xiaowen X   Zhao Qingchun Q  

ACS omega 20220830 36


The pathogenesis of Alzheimer's disease (AD) is very complex, and there are many hypotheses. Therefore, the development of a multi-target-directed-ligand may be an effective therapeutic strategy. Our previous study showed that notopterol (a natural product from <i>Notopterygium</i>) is a dual BACE1/GSK3β inhibitor. In this study, we designed and synthesized 48 notopterol derivatives with furacoumarin as a scaffold in order to enhance their balanced AChE/BACE1/GSK3β inhibitory activity. Fortunate  ...[more]

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