Structure-Activity Relationship of Phytotoxic Natural 10-Membered Lactones and Their Semisynthetic Derivatives

Ten-membered lactones (nonenolides) demonstrate phytotoxic, antimicrobial, and fungicidal activity promising for the development of natural product-derived pesticides. The fungus Stagonospora cirsii is able to produce phytotoxic stagonolides A (1), J (2), K (3) and herbarumin I (4) with high yield. The aim of this study was to create a set of structurally related nonenolides and to reveal the structural features that affect their biological activity. Stagonolide A (1) and C-7 oxidized stagonolide K (11) showed the highest phytotoxicity in leaf puncture assay and agar seedlings assay. The oxidation of C-7 hydroxyl group (as in 1, acetylstagonolide A (10) and (11) led to the manifestation of toxicity to microalgae, Bacillus subtilis and Sf9 cells regardless of the configuration of C-9 propyl chains (R in 1 and 10, S in 11). C-7 non-oxidized nonenolides displayed none or little non-target activity. Notably, 7S compounds were more phytotoxic than their 7R analogues. Due to the high inhibitory activity against seedling growth and the lack of side toxicity, mono- and bis(acetyl)- derivatives of herbarumin I were shown to be potent for the development of pre-emergent herbicides. The identified structural features can be used for the rational design of new herbicides.

Automated summary

Ten-membered lactones demonstrate phytotoxic, antimicrobial, and fungicidal activity, with Stagonospora cirsii fungus producing phytotoxic stagonolides with high yield. The study aimed to create structurally related nonenolides and identify the structural features that affect their biological activity. The oxidation of C-7 hydroxyl group was found to be a key structural feature affecting the phytotoxicity of nonenolides, with 7S compounds showing higher phytotoxicity compared to their 7R analogues.