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

Hyperelodeoines A and B (1 and 2, respectively), two unprecedented seco-prenylated butylphloroglucinol derivatives, along with two known analogues (3 and 4), were identified from Hypericum elodeoides. Compounds 1 and 2, 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, 2 and 4 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 2 and 4. In vivo zebrafish studies further demonstrated that 2 and 4 exhibited remarkable anti-Alzheimer's disease (AD) effects with no detectable toxicity or teratogenicity. Thus, 2 and 4 could activate PPARγ and show promise as anti-AD agents.