Biatractylonoids A–E, Five Eudesmane-Type Sesquiterpenoid Dimers from the Rhizomes of Atractylodes macrocephala with Anti-inflammatory Activity

Natural products, particularly dimeric sesquiterpenoids, have garnered significant interest among organic chemists due to their intriguing biological properties. In this study, we isolated five novel dimeric eudesmane-type sesquiterpenoids, biatractylonoids A–E ( 1 – 5 ), from the rhizomes of Atractylodes macrocephala . The structures and absolute configurations of these compounds were elucidated by comprehensive spectroscopic analysis, chemical calculations, and single-crystal X-ray diffraction. Compounds 1 – 4 exhibit a previously unreported dimerization pattern, featuring an unique 2-oxaspiro[4.4]nonane moiety. Notably, 4 possesses an unprecedented heptacyclic ring system with a unique 6/6/5/5/5/5/6 arrangement, fused to two monomers via a novel dimerization pattern that includes a five-membered O -heterocyclic ring. 5 results from the linkage of an eudesmane-type sesquiterpenoid to atractylone through furfuryl alcohol. Biologically, 1–3 exhibited inhibitory activities against NO release with IC 50 values ranging from 16.1 to 21.0 μM, as compared with the positive control ( l -NAME, IC 50 value: 18.8 μM). Furthermore, compound 1 markedly decreased the secretion of TNF-α, IL-6, and IL-1β in LPS-induced RAW 264.7 cells in a dose-dependent manner. Mechanistic studies revealed that 1 potentially targeted PLD1 through hydrogen bonding interactions with Val792 and Arg923, thereby regulating its biological function. These compounds exhibited unique structures and significant anti-inflammatory activity, and PLD1 was identified as a potential target of compound 1 .