Synthesis of 1-hydroxy-3-O-substituted xanthone derivatives and their structure-activity relationship on acetylcholinesterase inhibitory effect

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.