Anti-Neuroinflammatory Eremophilane Sesquiterpenoids from Marine-Derived Fungus Phoma sp. DXH009

Three new eremophilane sesquiterpenoids (1-3), together with six known analogues, were isolated from the marine-derived fungus Phoma sp. DXH009. Their structures were elucidated through detailed NMR and MS spectroscopic analysis, and the absolute configurations of 1-4 were determined by conformational analysis and quantum chemical TDDFT-ECD calculation. Their anti-neuroinflammatory activities were evaluated using the lipopolysaccharide (LPS)-induced BV2 microglial cells. The results indicated that compound 5 (dihydrosporogen AO-1) exhibited significant inhibitory effects on the production of nitric oxide (NO) levels (EC₅₀ = 3.11 μM) with less cytotoxicity, leading to a reversal effect in inducing microphage polarization in LPS-treated BV2 microglial cells. These were correlated with suppressions of the canonical NF-κB pathway as well as the expression levels of key neuroinflammatory markers, including COX2, TNF-α, IL-6, and IL-1β. Correspondingly, treating 5 in LPS-induced mice efficiently ameliorated neuroinflammation in the tissues of the cortex and hippocampus. These findings suggest that eremophilane sesquiterpenoid 5 could be a potential candidate for the development of anti-neuroinflammatory drugs.