Seco-Prenylated Butylphloroglucinol Derivatives from <i>Hypericum elodeoides</i> and Their Anti-Alzheimer’s Disease Activities

Hyperelodeoines A and B (<b>1</b> and <b>2</b>, respectively), two unprecedented seco-prenylated butylphloroglucinol derivatives, along with two known analogues (<b>3</b> and <b>4</b>), were identified from <i>Hypericum elodeoides</i>. Compounds <b>1</b> and <b>2</b>, featuring a 7/5 fused ring core, represent the first examples of phloroglucinol ring-opening products derived from the [3.2.1]-type bicyclic polyprenylated acylphloroglucinols (BPAPs). Notably, <b>2</b> and <b>4</b> significantly upregulated ABCA1 and ApoE protein levels in BV-2 cells. Dual-luciferase reporter assay, CETSA, and SPR analysis identified PPARγ as the potential target of <b>2</b> and <b>4</b>. In vivo zebrafish studies further demonstrated that <b>2</b> and <b>4</b> exhibited remarkable anti-Alzheimer's disease (AD) effects with no detectable toxicity or teratogenicity. Thus, <b>2</b> and <b>4</b> could activate PPARγ and show promise as anti-AD agents.