Goondastatins and Goondazines: Triamide-Hydroxamate and Piperazine Anthelmintics from Australian Pasture Soil-Derived Actinomadura and Streptomyces spp.

Chemical investigation of an Australian pasture soil-derived Actinomadura sp. prioritized for anthelmintic properties, led to the isolation and characterization of four new triamide-hydroxamates, goondastatins A1–D1 ( 1–4 ), with structures assigned on the basis of detailed spectroscopic analysis and chemical degradations/derivatization (Marfey’s and Mosher analyses). The corresponding oxazoles, goondastatins A2–D2 ( 1a–4a ) were also detected and tentatively identified. An expanded investigation of four additional Australian pasture soil-derived Streptomyces spp., also prioritized for anthelmintic properties, led to the discovery of goondastatin E2 ( 5 ) as a hydrolysis handling artifact of the known cometabolite kasichelin C ( 5a ), two new piperazines, goondazines A ( 6 ) and B ( 9 ), and the known piperazines XR334 ( 7 ) and piperafizine A ( 8 ) with structures assigned by detailed spectroscopic and chemical analysis. While much of the anthelmintic properties of the pasture soil actinomycete could be attributed to known natural product classes (e.g., maduramicins and piericidins), goondastatin E1 ( 5 ) exhibited moderate and selective inhibition of dog heartworm Dirofilaria immitis microfilariae motility (EC 50 = 4.1 μg/mL). Goondazine A ( 6 ), in contrast, exhibited moderate inhibition of livestock (ruminant) gastrointestinal nematode Hemonchus contortus L1–L3 larval development (EC 50 = 1.2 μg/mL) and weak inhibition of D. immitis microfilariae motility (EC 50 = 15 μg/mL).