Discovery of Antibacterial Azaphilone Hybrid Metabolites from Marine-Derived <i>Aspergillus terreus</i> PPS1

Three novel azaphilone hybrids (<b>1</b>-<b>3</b>) with two types of structural units, along with four known compounds (<b>4</b>-<b>7</b>), were obtained from the marine sediment-derived fungus <i>Aspergillus terreus</i> PPS1. Asperbenzophilone A (<b>1</b>) features an unprecedented 6/6/6/6 ring system containing a hemiketal group. Butyropyranones I and II (<b>2</b> and <b>3</b>) are equipped with an azaphilone fragment preasperpyranone and a butyrolactone, which are connected through ether bonds. Comprehensive spectroscopic techniques, ECD calculations, and deduction of biosynthetic pathways were used to confirm the planar structures and absolute configurations of the new compounds. Compound <b>2</b> displayed significant anti-MRSA activity. Additionally, compound <b>2</b> exhibited moderate cytotoxic activity on human tumor cell lines 786-O, 5637, MCF-7, A-673, and 293T and medium inhibitory activity against the SARS-CoV-2 main protease (M^pro/3CL^pro).