# Goondoxazoles A–C: Anthelmintic Spiroketal Polyketide Alkaloids and Other Benzoxazoles from Australian Pasture Soil-Derived Streptomyces spp

## TL;DR

Scientists discovered new natural compounds from soil bacteria that show strong potential to combat parasitic worms, with some simpler versions being just as effective.

## Contribution

The discovery of goondoxazoles A–C and their anthelmintic activity against Dirofilaria immitis, along with insights into structural activity relationships.

## Key findings

- Goondoxazoles A–C are new spiroketal polyketide alkaloids with anthelmintic properties.
- Benzoxazole-containing compounds (2 and 3) showed higher potency against D. immitis microfilariae than ring-opened analogs.
- A simpler benzoxazole natural product (A-33583) demonstrated comparable or improved activity against D. immitis larvae.

## Abstract

Background/Objectives/Methods: A bioassay-informed investigation of the Australian pasture soil-derived Streptomyces sp. S4S-00193A39 yielded the anthelmintic principals as three new spiroketal polyketide alkaloids, goondoxazoles A–C (1–3), with structures assigned by detailed spectroscopic analysis. Results: A structure–activity relationship based on the ability to inhibit the motility of Dirofilaria immitis microfilariae (mf) revealed a positive correlation for the benzoxazole moiety present in 2 and 3 (EC50 55–85 nM) versus the ring-opened aminobenzoic acid moiety evident in 1 (EC50 1.38 µM). This hypothesis was strengthened by extension of the SAR assessment to the known benzoxazole natural products A-33583 (12), UK-1 (13) and nataxazole (14), and the new analogue 5-hydroxynataxazole (15), which were isolated in our lab from three additional Australian pasture soil-derived Streptomyces spp. Of note, while the benzoxazole methyl esters 13–15 exhibited approximately 9- to 65-fold lower potency against D. immitis mf compared with 2 and 3, the carboxylic acid substituted benzoxazole 12 displayed comparable activity (EC50 72 nM) against D. immitis mf, and >5-fold improved potency against D. immitis L4 larvae (EC50 0.43 µM). Conclusions: These observations reveal the promising anthelmintic potential (against D. immitis) for the new structurally complex and chiral goondoxazoles (e.g., 2 and 3), and demonstrate that this effect can be replicated, even improved, by simpler, achiral benzoxazole microbial natural products (e.g., 12).