Abstract

This study focused on the synthesis of 1,3-dihydroxyxanthone (1) and its new derivatives with alkyl (2a–2f), alkenyl (2 g–2k), alkynyl (2 l–2n), and alkylated phenyl (2o–2r) groups at C3 position. The structures of these compounds were confirmed by MS, NMR, and FTIR spectroscopic data. All the substituted xanthones (2a–2r) 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.

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 ( 2a – 2f )、烯基 ( 2 g – 2k )、炔基 ( 2 l – 2n ) 和烷基化苯基 ( 2o – 2r ) ) 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 ( 2a – 2r ) 均表现出比1更强的乙酰胆碱酯酶 (AChE) 抑制活性。化合物2g和2j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。