Benzofurans from Styrax agrestis As Acetylcholinesterase Inhibitors: Structure–Activity Relationships and Molecular Modeling Studies

An extract of Styrax agrestis fruits, collected in Vietnam, significantly inhibited acetylcholinesterase (AChE) in vitro. Bioassay-guided fractionation revealed three new egonol-type benzofurans: egonol-9(Z),12(Z) linoleate (1), 7-demethoxyegonol-9(Z),12(Z) linoleate (2), and 7-demethoxyegonol oleate (4). Ten known egonol-type benzofurans were also isolated (3, 5, 6–13). In order to better understand structure–activity relationships in this series, egonol derivatives 14–19 were prepared by chemical modifications and evaluated for their inhibition of AChE, butyrylcholinesterase (BChE), and AChE-induced Aβ aggregation. Compounds 1–4 were the most potent inhibitors of the series, which exhibited inhibitory activity against AChE (IC50 1.4–3.1 μM) and, for 1, Aβ aggregation (77.6%). Molecular docking studies were also performed to investigate interaction of these compounds with the active site of AChE.