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Probing simple structural modification of α‐mangostin on its cholinesterase inhibition and cytotoxicity
Author(s) -
Khaw KooiYeong,
Kumar Pravin,
Yusof Siti Rafidah,
Ramanathan Surash,
Murugaiyah Vikneswaran
Publication year - 2020
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.202000156
Subject(s) - butyrylcholinesterase , acetylcholinesterase , chemistry , cholinesterase , cytotoxicity , aché , toxicity , stereochemistry , enzyme , biochemistry , pharmacology , inhibitory postsynaptic potential , in vitro , organic chemistry , biology , neuroscience
α‐Mangostin has been reported to possess a broad range of pharmacological effects including potent cholinesterase inhibition, but the development of α‐mangostin as a potential lead compound is impeded by its toxicity. The present study investigated the impact of simple structural modification of α‐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 µM, but not butyrylcholinesterase (BChE) inhibitory activities, compared with α‐mangostin, a dual inhibitor (IC 50 : AChE, 2.48 µM; BChE, 5.87 µM). Dialkylation of α‐mangostin produced AChE selective inhibitors that formed hydrophobic interactions at the active site of AChE. Interestingly, all four dialkylated derivatives of α‐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 α‐mangostin. Taken together, modification of the hydroxyl groups of α‐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.