Three New α-Pyrone Derivatives with Antiepileptic Activity from the Marine Actinomycete Nocardiopsis sp. NBUDK19

Epilepsy is a serious brain disease that urgently needs new drugs to treat it. In this study, three new α -pyrone derivatives, nocardipones A − C ( 1 − 3 ), were isolated from the sponge-associated actinomycete Nocardiopsis sp. NBUDK19 guided by anti-epileptic bioactivity using an in vivo zebrafish model. Compounds 1  −  3 were isolated and purified by silica gel column chromatography combined with semi-preparative HPLC. The structures of 1 − 3 were elucidated by UV, HRESIMS, NMR spectroscopic analysis, optical rotation, and computational chemical calculations. Our pharmacological study showed that compounds 1 − 3 exhibited notable reductions in seizure-like locomotor activity at 5 μg/mL. The qPCR analysis showed that compounds 1 − 3 significantly regulated the mRNA expression levels of c-fos and genes associated with GABAergic-glutamatergic signaling, including gria1b and gat1 . The molecular docking revealed that compounds 1 − 3 strongly binding to 4-aminobutyric acid transaminase, with binding energies of − 7.3, − 7.8, and − 7.3 kcal/mol, respectively. This work enriches bioactive drug discovery to treat epilepsy and illustrates an underlying pharmacological and molecular mechanism of these natural α -pyrones.