Synthesis, fungicidal activity, and DFT calculation of novel amide derivatives based on the metabolite of cyprodinil.

Pesticide metabolites have become important lead sources for the development of new agrochemicals. Cyprodinil is a widely used systemic fungicide, and its major photodegradation metabolite TPs3 remain underexplored. Herein, TPs3 was firstly synthesized, and a series of its novel amide derivatives 7a-7m were designed and prepared. All compounds were evaluated for antifungal activity against four common phytopathogenic fungi. Bioassays showed that derivative 7c exerted excellent inhibitory activity against sclerotinia sclerotiorum, which was comparable to that of commercial cyprodinil. Electrostatic potential (ESP) and density functional theory (DFT) calculations were performed to explore biological activity differences of this TPs3 derivatives at atomic and electronic levels. In silico toxicological prediction suggested that most derivatives presented low toxicity toward non-target organisms. This work not only establishes an effective synthetic method for cyprodinil metabolite TPs3, but also provides a feasible strategy for developing novel fungicides by exploiting pesticide metabolites as lead skeletons.