Khaw_2020_Arch.Pharm.(Weinheim)__e2000156

alpha-Mangostin has been reported to possess a broad range of pharmacological effects including potent cholinesterase inhibition, but the development of alpha-mangostin as a potential lead compound is impeded by its toxicity. The present study investigated the impact of simple structural modification of alpha-mangostin on its cholinesterase inhibitory activities and toxicity toward neuroblastoma and liver cancer cells. The dialkylated derivatives retained good acetylcholinesterase (AChE) inhibitory activities with IC(50) values between 4.15 and 6.73 muM, but not butyrylcholinesterase (BChE) inhibitory activities, compared with alpha-mangostin, a dual inhibitor (IC(50) : AChE, 2.48 muM; BChE, 5.87 muM). Dialkylation of alpha-mangostin produced AChE selective inhibitors that formed hydrophobic interactions at the active site of AChE. Interestingly, all four dialkylated derivatives of alpha-mangostin showed much lower cytotoxicity, being 6.4- to 9.0-fold and 3.8- to 5.5-fold less toxic than their parent compound on neuroblastoma and liver cancer cells, respectively. Likewise, their selectivity index was higher by 1.9- to 4.4-fold; in particular, A2 and A4 showed improved selectivity index compared with alpha-mangostin. Taken together, modification of the hydroxyl groups of alpha-mangostin at positions C-3 and C-6 greatly influenced its BChE inhibitory and cytotoxic but not its AChE inhibitory activities. These dialkylated derivatives are viable candidates for further structural modification and refinement, worthy in the search of new AChE inhibitors with higher safety margins.