Tetramic acid and sesquicillin derivatives with anti-neuroinflammatory activity from Penicillium citrinum SMUC020.

Six previously undescribed 3-decalinoyltetramic acid (3-DTA) derivatives Penicitriequitins A-F (1-6), one previously undescribed meroterpenoid Sesquicillin G (7), together with three previously described meroterpenoids were isolated from rhizosphere fungus Penicillium citrinum SMUC020. Their structures were elucidated by extensive analysis of NMR spectroscopic data, modified Mosher's method, and quantum computed ECD calculations. The L-alanine in the tetramic acid moiety was established by Marfey's method. Compounds 1-6 feature an unusual oxidation pattern at C-3, which has rarely been observed in DTA related natural products. Anti-inflammatory activity screening was performed to evaluate the inhibitory effects of these compounds on the production of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Further mechanistic studies showed that compound 5 reduced the phosphorylation of NF-κB p65 and IκBα, while CETSA indicated an alteration in the thermal stability of NF-κB. These findings support an association between the activity of compound 5 and modulation of NF-κB/IκBα signaling, without establishing direct protein binding. This study expands the structural diversity of equisetin-type trans-DTAs and provides a basis for further exploration of their structure-activity relationships and biosynthetic mechanisms.