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

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