Goondicones A–H: Spiro-Isoindolinone Heartworm Anthelmintics from an Australian Pasture-Soil-Derived Streptomyces sp.

Abstract

Background/Objectives: There is an urgent need for new and improved anthelmintics that are not constrained by existing resistance pathways and that can safeguard the health and welfare of animals. Methods: An integrated platform of chemical, bioassay, and cultivation profiling applied to a library of microbes isolated from Australian livestock pasture soil was used to detect and guide the production, isolation, characterization, identification, and evaluation of new natural products with anthelmintic properties. Results: A global natural products social (GNPS) molecular network analysis of 110 Australian pasture-soil-derived microbial extracts prioritized for antiparasitic activity identified unique molecular families in the extract of Streptomyces sp. S4S-00185A06, a strain selectively active against Dirofilaria immitis microfilariae. UPLC-DAD analysis identified metabolites with unique UV-vis chromophores and unprecedented molecular formulas. A chemical investigation of Streptomyces sp. S4S-00185A06 yielded goondicones A–H (1–8) as new examples of a rare class of spiro-isoindolinones, with structures assigned on the basis of detailed spectroscopic analysis, ECD calculations, and biosynthetic considerations. Conclusions: While goondicones 1–8 exhibit little to no in vitro inhibitory activity against Gram-positive, Gram-negative, and/or fungal pathogens, human carcinoma cells, or the livestock gastrointestinal parasite Haemonchus contortus L1–L3 larvae, 5 and 6 (and, to a lesser extent, 1) inhibit the motility of heartworm Dirofilaria immitis microfilaria (IC50 10–11 μM). A structure activity relationship analysis based on the co-metabolites 1–8 suggests that (i) an 8-OH is preferable to 8–oxo moiety, (ii) 20-NMe and 3-OH moieties are essential, and (iii) C-9 epimerization exerts no discernible impact on in vitro potency.