Synthesis and Biological Evaluation of 3-Benzisoxazolyl-4-indolylmaleimides as Potent, Selective Inhibitors of Glycogen Synthase Kinase-3β

Molecules

Qing Ye²  Meng Li²  Yubo Zhou³  Tao Pang³  Lei Xu³  Jiayi Cao³  Liang Han²  Yujin Li²  Weisi Wang¹  Jianrong Gao² 

[1] ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China, E-Mail:;State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310032, Zhejiang, China; E-Mails:;The National Center for Drug Screening, Shanghai 201203, China; E-Mails:

关键词: 3-benzisoxazolyl-4-indolylmaleimides;    synthesis;    GSK-3β;    biological activity;    docking;    SAR;   

DOI  :  10.3390/molecules18055498

来源: mdpi

【 摘 要 】

A series of novel 3-benzisoxazolyl-4-indolyl-maleimides were synthesized and evaluated for their GSK-3β inhibitory activity. Most compounds exhibited high inhibitory potency towards GSK-3β. Among them, compound 7j with an IC₅₀ value of 0.73 nM was the most promising GSK-3β inhibitor. Preliminary structure-activity relationships were examined and showed that different substituents on the indole ring and N¹-position of the indole ring had varying degrees of influence on the GSK-3β inhibitory potency. Compounds 7c, 7f, 7j-l and 7o-q could obviously reduce Aβ-induced Tau hyperphosphorylation by inhibiting GSK-3β in a cell-based functional assay.

【 授权许可】

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© 2013 by the authors; licensee MDPI, Basel, Switzerland.