Pseudo-natural products (PNPs) are new arrangements of natural product (NP) fragments, creating chemical spaces that extend beyond those explored by nature and are unattainable via known biosynthetic pathways. Herein, we establish the design principles for agrochemically-active PNPs based on characteristic pesticide features. We systematically applied this strategy to discover PNP agricultural fungicides, opening up a broad new avenue for developing novel NP-derived pesticides. We designed perilloxazole PNPs by integrating cyclohexene and isoxazoline fragments. Cheminformatics analysis demonstrates that perilloxazole PNPs combine the advantageous properties of NPs and pesticides. Biological evaluation reveals that perilloxazole represents a new chemotype of sterol biosynthesis inhibitor with low toxicity to non-target organisms, providing a foundation for the discovery of superior green fungicides. Perilloxazole PNPs exhibit notable control efficacy against major crop diseases that cause severe agricultural losses, holding broad application prospects and high market potential.
Lei et al. (Wed,) studied this question.