Goondicones I–K and Cratermycins A–D: Cultivation Profiling Enabled the Search for New Anthelmintics from an Australian Pasture Soil-Derived <i>Actinomadura</i> sp.

A detailed chemical investigation of the Australian pasture soil-derived <i>Actinomadura</i> sp. S4S-00069B10, utilizing optimized cultivation on four different solid-phase media (M1, IMA, D400, and YEME), yielded the new isoindolinone goondicones I-K (<b>1</b>-<b>3</b>) and anthra-γ-pyrone cratermycins A-D (<b>4</b>-<b>7</b>). Structures were assigned to <b>1</b>-<b>7</b> on the basis of detailed spectroscopic, ECD, and X-ray analyses as well as chemical transformations and biosynthetic considerations. The goondicones <b>1</b>-<b>3</b> are especially noteworthy in that they feature an unprecedented carbo-heterocyclic framework, with <b>1</b> and <b>2</b> undergoing a facile keto-enol-mediated equilibration to a 1:3 mixture (of C-13 epimers) that exhibits promising anthelmintic properties against the dog heartworm <i>Dirofilaria immitis</i> microfilariae (EC₅₀ 1.1 μM) and L4 larvae (EC₅₀ 1.3 μM). Notably, this activity is accompanied by measurable mammalian cytotoxicity, indicating a narrow therapeutic window. Together, these findings highlight the chemical novelty of <i>Actinomadura</i>-derived metabolites, and their value as structurally unique anthelmintics leads to further optimization.