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, MAE ΔΔδ ), DU8+, electron-capture detector, detection (EC)D calculations, Rh 2 (OCOCF 3 ) 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.