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

Xanthones are valuable compounds in drug design and development, attributed to their multi-dimensional pharmacological properties, including anti-cancer, anti-bacterial, anti-malarial, anti-inflammatory and anti-cholinesterase. This study focused on the synthesis of 1,3-dihydroxyxanthone (1) and its new 1-hydroxy-3-O-substituted derivatives with alkyl (2a-2f), alkenyl (2g-2k), alkynyl (2l-2n) and alkylated phenyl (2o-2r) groups and were synthesised in a high percentage yield of >70%, except for 2l and 2p. Their structures were confirmed by MS, NMR and FTIR spectroscopic techniques. The evaluation of acetylcholinesterase (AChE) inhibitory activities showed that all the substituted xanthones (2a-2r) are more potent than 1. Compounds 2g and 2j are the strongest AChE inhibitors with the IC50 values of 20.8 and 21.5 μM and their enzyme kinetic analyses indicated that these derivatives possess a mixed-mode inhibition, where they targeted both the active sites and allosteric sites of AChE. Molecular docking study revealed that 2g binds favourably to the active site of AChE via π–π stacking and hydrogen bonding, in addition to π-alkyl interaction and alkyl interaction from the substituent group. The xanthone derivatives are identified as potential lead compounds for further development of Alzheimer’s disease treatments.