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Synthesis of 1-hydroxy-3-O-substituted xanthone derivatives and their structure-activity relationship on acetylcholinesterase inhibitory effect
Natural Product Research ( IF 1.9 ) Pub Date : 2022-11-18 , DOI: 10.1080/14786419.2022.2137800
Vincentsia Vienna Vanessa 1 , Soek Sin Teh 2 , Kok Wai Lam 3 , Siau Hui Mah 1, 4
Affiliation  

Abstract

This study focused on the synthesis of 1,3-dihydroxyxanthone (1) and its new derivatives with alkyl (2a2f), alkenyl (2 g2k), alkynyl (2 l2n), and alkylated phenyl (2o2r) groups at C3 position. The structures of these compounds were confirmed by MS, NMR, and FTIR spectroscopic data. All the substituted xanthones (2a2r) showed significantly stronger acetylcholinesterase (AChE) inhibitory activities than 1. Compounds 2g and 2j exhibited the strongest activities with the IC50 values of 20.8 and 21.5 μM and their enzyme kinetic analyses indicated a mixed-mode inhibition. Molecular docking study revealed that 2g binds favourably to the active site of AChE via π–π stacking and hydrogen bonding from the xanthone ring, in addition to π-alkyl interaction from the substituent group. These xanthone derivatives are potential lead compounds to be further developed into Alzheimer’s disease drugs.



中文翻译:

1-羟基-3-O-取代呫吨酮衍生物的合成及其对乙酰胆碱酯酶抑制作用的构效关系

摘要

本研究重点合成 1,3-二羟基氧杂蒽酮 ( 1 ) 及其新衍生物,包括烷基 ( 2a2f )、烯基 ( 2 g2k )、炔基 ( 2 l2n ) 和烷基化苯基 ( 2o2r ) ) 组在 C3 位置。这些化合物的结构通过 MS、NMR 和 FTIR 光谱数据得到证实。所有取代的氧杂蒽酮 ( 2a2r ) 均表现出比1更强的乙酰胆碱酯酶 (AChE) 抑制活性。化合物2g2j表现出最强的活性,IC 50值为20.8和21.5 μM,它们的酶动力学分析表明存在混合模式抑制。分子对接研究表明,除了取代基的π-烷基相互作用外,2g还通过π-π堆积和氧杂蒽酮环的氢键与AChE的活性位点有利地结合。这些呫吨酮衍生物是潜在的先导化合物,可进一步开发为阿尔茨海默病药物。

更新日期:2022-11-18
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