Bioassay-guided discovery of anti-inflammatory sesquiterpenoids from Lindera aggregata (Sims) Kosterm

A bioassay-guided phytochemical investigation on the ethyl acetate extract from the roots of Lindera aggregata (Sims) Kosterm led to the isolation of fifteen sesquiterpenoids, comprising twelve previously undescribed compounds, linderasins A-L (1-12), and three known analogues (13-15). Their structures were elucidated by comprehensive spectroscopic analyses, quantum chemical calculations, and single-crystal X-ray diffraction. Notably, compounds 1 and 2 were unusual homolindenane sesquiterpenoids bearing an additional carbon at C-11 in 1 and C-8 in 2, while compounds 3 and 11 were 12,13-bisnorlindenane and 15-noreudesmane sesquiterpenoids, respectively. Compounds 13-15 were isolated for the first time from a plant of the order Laurales. All isolates were evaluated for their anti-inflammatory activity in lipopolysaccharide-stimulated RAW264.7 macrophages. In a preliminary screening, compounds 2, 3, 7, and 10 showed moderate inhibition of nitric oxide (NO) production without significant cytotoxicity. Further RT-qPCR analysis revealed that compound 10 dose-dependently downregulated the mRNA expression of key inflammatory mediators, including IL-1β, IL-6, iNOS, and COX-2. Collectively, this study expanded the chemical diversity of sesquiterpenoids from L. aggregata and identified compound 10 as a promising anti-inflammatory lead that merits further mechanistic and in vivo investigation.