Rapid Discovery of Guaiane-Type Sesquiterpenoids with Rare Ring Skeletons from Daphne aurantiaca using Molecular Networking Together with MS-DIAL and Self-Built Database

Under the guidance of the approach that integrates molecular networking, MS-DIAL and self-built database, 11 undescribed guaiane-type sesquiterpenoids (1–11) along with four known analogs (12–15) were targeted and isolated from Daphne aurantiaca. Among these, dapurant A–B (1–2) were unusual guaiane-type sesquiterpenoid dimers consisting of two guaiane-type sesquiterpenoids with different ring skeletons, and dapurant C–D (3–4) represented rare chlorinated guaiacane-type sesquiterpenoids. Their chemical structures and configurations were established via NMR spectroscopy analysis, computer-assisted structure elucidation methods, density functional theory (DFT) NMR calculations with suitable analysis methods (custom DP4+ analysis, CP3 analysis, MAEΔΔδ), DU8+, electron-capture detector, detection (EC)D calculations, Rh2(OCOCF3)4-induced ECD analysis along with semisynthesis method. The network pharmacology analysis prompted us to explore the cholinesterase inhibitory activity and anti-Aβ aggregation activity of the isolates in vitro and in silico. The bioactivity evaluation results highlighted the prospects of 1, 13, and 14 as novel categories of neurological agents.