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.