A pro-natural product design strategy affords ester-based green fungicide candidates

Natural products (NPs) serve as both inspirations and resources for the discovery of bioactive compounds. However, their application in green agrochemical discovery faces limitations such as low activity, short duration of efficacy, potential toxicity and residue issues from structural modifications, and constraints in exploring chemical and biological space. Here, we propose the concept and design principles of pro-natural products (PrNPs), which effectively address these limitations and open a broad avenue for bioactive compound discovery. PrNPs are functional compounds designed to degrade into NPs under application conditions. Using this strategy, we designed and synthesized a structurally diverse ester-based PrNP collection with 170 members by combining natural acids and alcohols and found a promising green fungicide candidate, PrNP 6E, with excellent control efficacy against major plant diseases such as rapeseed Sclerotinia stem rot, rice sheath blight, and apple Valsa canker. Cheminformatic analysis, antifungal activity, degradation behavior, and safety assessment reveal that 6E combines the advantageous properties of both NPs and agrochemicals and exhibits suitable duration of efficacy, controllable degradation into NPs after fulfilling its function, broad safety, and environmental compatibility. The PrNP strategy shows great potential in enhancing the efficiency of finding green agrochemicals with novel chemotypes and mechanisms of action and in promoting sustainable development of agriculture.