Cyclopeptide Avellanins D–O with Antimalarial Activity from the Mariana Trench Anemone-Derived <i>Hamigera ingelheimensis</i> MSC5

Marine microorganisms are a treasure trove of natural products, especially those in extreme marine environments, which may produce novel natural products. Herein, biosynthetic gene cluster analysis combined with an integrated metabolomic strategy incorporating matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS), nuclear magnetic resonance (NMR), and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) based Global Natural Products Social Molecular Networking (GNPS) was used to discover new compounds from the Mariana trench anemone-derived fungus <i>Hamigera ingelheimensis</i> MSC5. As a result, 12 new cyclic pentapeptides, avellanins D-O (<b>1</b>-<b>12</b>), were isolated, together with a known cyclic pentapeptide avellanin C (<b>13</b>). All the structures and absolute configurations were elucidated using NMR, mass spectrometry, X-ray diffraction analysis, and Marfey's method. A plausible biosynthetic pathway for the avellanins was proposed based on the gene cluster analysis of <i>H. ingelheimensis</i> MSC5. Bioassay revealed that compound <b>6</b> exhibited potent antimalarial activity with an IC₅₀ value of 0.19 ± 0.09 μM.