Synthesis and Herbicidal Assessment of 3‑Acyltetramic Acid Prodrugs

Herbicides are widely used in conventional agriculture to maintain crop yields and facilitate no-till farming. However, herbicide use is increasingly restricted due to concerns around (eco)-toxicity and environmental persistence. A second major challenge is the increasing frequency of herbicide resistance, driven in part by overreliance on a narrow range of active ingredients and mechanisms of action. Biologically derived products are gaining more interest as lead compounds in the development of novel herbicidal products. Previous research by our group drew the attention to 3-acyltetramic acids of bacterial origin as a promising class of biologically derived herbicidal compounds. A potential opportunity to improve the activity, stability or other desirable properties of bioactive molecules lies in the application of the prodrug concept. Prodrugs are biologically inactive analogues of the target compound that is activated in the target tissue, releasing the active compound. In this work, potential proherbicidal derivatives of the most active 3-acyltetramic acid in our library were synthesized and screened for their herbicidal activity using Solanum lycopersicum leaf disks and high-resolution monitoring of photosynthetic activity as a sensitive proxy for phytotoxicity. It was found that some of the assessed 3-enaminetetramic acid analogues seemed to show a delayed and systemic herbicidal activity on leaf disks, indicating proherbicidal activity. However, further evaluation of these proherbicides in spray tests with Amaranthus retroflexus showed the original molecule outperformed the proherbicides. Together, these findings reveal interesting insights for further investigation on the activity of these compounds and further highlight that care should be taken when translating results from in vitro assays to further testing.