Alzheimer's disease is a neurodegenerative disorder that results in progressive and irreversible
central nervous system impairment, which has become one of the severe issues recently. The most
successful approach of Alzheimer’s treatment is the administration of cholinesterase inhibitors to prevent
the hydrolysis of acetylcholine and subsequently improve cholinergic postsynaptic transmission.
This review highlights a class of heterocycles, namely xanthone, and its remarkable acetylcholinesterase
inhibitory activities. Naturally occurring xanthones, including oxygenated, prenylated, pyrano, and
glycosylated xanthones, exhibited promising inhibition effects towards acetylcholinesterase. Interestingly,
synthetic xanthone derivatives with complex substituents such as alkyl, pyrrolidine, piperidine,
and morpholine have shown greater acetylcholinesterase inhibition activities. The structure-activity
relationship of xanthones revealed that the type and position of the substituent(s) attached to the xanthone
moiety influenced acetylcholinesterase inhibition activities where hydrophobic moiety will lead
to an improved activity by contributing to the π-π interactions, as well as the hydroxy substituent(s) by
forming hydrogen-bond interactions. Thus, further studies, including quantitative structure-activity
relationship, in vivo and clinical validation studies are crucial for the development of xanthones into
novel anti-Alzheimer's disease drugs.