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

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 IC 50 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.