Phaeosphaones: Tyrosinase Inhibitory Thiodiketopiperazines from an Endophytic Phaeosphaeria fuckelii

Phaeosphaeria fuckelii, an endophytic fungus associated with the herbal medicine Phlomis umbrosa, produced four new thiodiketopiperazine alkaloids, phaeosphaones A–D (1–4), featuring an unusual β-(oxy)thiotryptophan motif, along with four known analogues, phaeosphaone E (5), chetoseminudin B (6), polanrazine B (7), and leptosin D (8). Their structures were elucidated by extensive spectroscopic data analysis, and their absolute configurations were determined by single-crystal X-ray diffraction and ECD calculations. Compounds 4, 6, and 8 were found to display mushroom tyrosinase inhibitory activity with IC50 values of 33.2 ± 0.2, 31.7 ± 0.2, and 28.4 ± 0.2 μM, respectively, more potent than that of the positive control, kojic acid (IC50 = 40.4 ± 0.1 μM). A molecular-docking study disclosed the π–π stacking interaction between the indole moiety of 8 and the His243 residue of tyrosinase.