Spiro-Polycyclic Polyprenylated Acylphloroglucinols from Hypericum monogynum and Their anti-Alzheimer's Disease...

Eight undescribed spiro-polycyclic polyprenylated acylphloroglucinols (PPAPs) with a 6/6/5 tricyclic architecture (1-8), together with eight known analogues (9-16), were isolated from Hypericum monogynum L. Their structures including absolute configurations were elucidated by spectroscopic analysis, single-crystal X-ray diffraction, and quantum chemical calculations. Biological evaluation revealed that compounds 4 and 16 showed potential as dual-target anti-Alzheimer's disease (AD) lead compounds, as they not only exhibited potent acetylcholinesterase (AChE) inhibitory activities but also induced peroxisome proliferator-activated receptor-γ transactivation and upregulated ATP-binding cassette transporter A1 expression. The in vivo anti-AD effects of 4 and 16 were evaluated by the zebrafish behavioral experiments. Compound 16 exhibited anti-AD effects with no detectable toxicity or teratogenicity, whereas 4 exhibited toxicity to zebrafish at 10 μM. These findings not only expand the chemical diversity of spiro-PPAPs but also underscore their potential as dual-target agents for AD treatment.