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

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 sp. S4S-00185A06, a strain selectively active against microfilariae. UPLC-DAD analysis identified metabolites with unique UV-vis chromophores and unprecedented molecular formulas. A chemical investigation of sp. S4S-00185A06 yielded goondicones A-H (-) 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 - 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 L1-L3 larvae, and (and, to a lesser extent, ) inhibit the motility of heartworm microfilaria (IC 10-11 μM). A structure activity relationship analysis based on the co-metabolites - 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.