Novel oxoisoaporphine-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation

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• 作者：Huang Tang ; Hai-Tao Zhao ; Shu-Ming Zhong ; Zhi-Yu Wang ; Zhen-Feng Chen ; ^{chenzfubc@yahoo.com} ; Hong Liang ; ^{hliang@gxnu.edu.cn}
• 关键词：Oxoisoaporphine derivatives ; Synthesis ; Acetylcholinesterase inhibitors ; 尾-amyloid aggregation
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 March, 2012
• 卷：22
• 期：6
• 页码：2257-2261
• 文件大小：687 K

摘要

A series of novel oxoisoaporphine-based inhibitors (10-aminoalkylamino-1-azabenzanthrone Ar-NH(CH₂)_nNR¹R²) of acetylcholinesterase (AChE) has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE) and AChE-induced 尾-amyloid (A尾) aggregation. The synthetic compounds exhibited high AChE inhibitory activity with IC₅₀ values in the submicromolar range in most cases. Non-competitive binding mode was found for these derivatives by the graphical analysis of steady-state inhibition data. Moreover, all compounds exhibit significant inhibitory activity on AChE-induced A尾 aggregation with inhibitory potency from 54.5%to 93.5%. Finally, six out of twelve synthetic compounds were predicted to be able to cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. The result encourages us to study this class of compounds thoroughly and systematically.