| Summary: | Nine previously undescribed brefeldin A (BFA) derivatives (1–9), together with one known compound 4-epi-brefeldin A (10), were isolated from an endophytic fungus Penicillium brefeldianum F4a. The chemical structures were elucidated using NMR and HRESIMS. ECD analysis and Mosher's method were used to confirm the absolute configurations of 1–9. The inhibitory activity of all isolated BFA derivatives (1–10) on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was evaluated in vitro. The bioassay results suggested that neobrefeldin (1) and brefeldin H (2) exhibited higher potent and selective AChE inhibitory activity (IC50 = 0.12 and 0.28 μM) than the therapeutic drug galantamine for Alzheimer's disease (AD) (IC50 = 0.66 µM), whereas only neobrefeldin (1) displayed weak inhibitory activity against BuChE (IC50 = 175.04 µM). Moreover, a molecular docking analyses was performed and showed compounds 1 and 2 were dual binding site AChE inhibitors. It is worth noting that neobrefeldin (1) showed a better binding affinity with the peripheral anionic site through the hydrogen bonding interaction with Tyr124 than brefeldin H (2), resulting in better AChE inhibitory activity. These findings not only provide a promising AChE inhibitor neobrefeldin (1) for developing agents against early AD, but also provide a valuable perspective for better understanding its AChE inhibition activity.
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