Discovery of Dual-Target Anti-Alzheimer’s Filicinic Acid-Based Meroterpenoids from Hypericum japonicum Thunb.

Seven undescribed filicinic acid-based meroterpenoids, hyperjaponiones A-G (1-7), along with a new natural product (hyperjaponione H, 8) and 10 known analogues (9-18), were isolated from Hypericum japonicum Thunb. Chiral separation of compound 1 afforded a pair of racemates (±)-1 (1a and 1b). Their structures were elucidated through a comprehensive spectroscopic analysis and quantum chemical calculations. Moreover, biological evaluation revealed that 8 activated peroxisome proliferator-activated receptor-γ (PPARγ) transcription and upregulated the level of ATP-binding cassette transporter A1 (ABCA1), showing promise in promoting β-amyloid (Aβ) clearance. Surface plasmon resonance analysis indicated that 8 might interacted with the PPARγ ligand-binding domain, with an estimated binding affinity (K_d) of 5.63 μM. Molecular docking study further predicted the binding mode of 8 to PPARγ. Additionally, 8 was found to inhibit β-site amyloid precursor protein cleaving enzyme 1 (BACE1) activity, showing potential in reducing Aβ generation. In an in vivo zebrafish model, 8 exhibited notable anti-Alzheimer's disease effects with no detectable toxicity or teratogenicity. Thus, 8 acts as a dual-target agent by both activating PPARγ and inhibiting BACE1, highlighting its potential as a novel therapeutic candidate for Alzheimer's disease.