Molecules, Vol. 29, Pages 1782: Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer & rsquo;s Disease

Molecules, Vol. 29, Pages 1782: Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer’s Disease Molecules doi: 10.3390/molecules29081782 Authors: Xiuyuan Wu Xiaotong Ze Shuai Qin Beiyu Zhang Xinnan Li Qi Gong Haiyan Zhang Zheying Zhu Jinyi Xu Alzheimer’s disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC50 = 0.223 μM) with pyrimidone compound 5 (GSK-3β: IC50 = 3 μM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3β (GSK-3β). The optimal compound 18a possessed potent dual AChE/GSK-3β inhibition (AChE: IC50 = 0.047 ± 0.002 μM, GSK-3β: IC50 = 0.930 ± 0.080 μM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research