Triazole Sulfonamide Derivates: Inhibitors of the bc1 Complex to Control Cucumber Downy Mildew.

Cucumber downy mildew (CDM), caused by Pseudoperonospora cubensis, is a destructive disease that affects greenhouse cucumbers and causes significant losses for growers. Amisulbrom, a triazole sulfonamide fungicide targeting the Qi site in the bc1 complex, has shown potential in effectively combating CDM. However, its detailed binding mode with the target is unclear. In this study, a three-dimensional (3D) structure of the bc1 complex from P. cubensis was built, and its interaction with amisulbrom was investigated by integrating molecular docking, molecular dynamics, and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) methods. Based on the binding mode of amisulbrom with the Pc-bc1 complex, a scaffold hopping strategy was performed, and compounds 11a-o and 12a-v were designed. Among them, compound 12g showed excellent fungicidal properties against CDM in field trials. The present work indicated that the oxime ether moiety could be further optimized for better results. Furthermore, compound 12g has the potential to serve as a lead compound in the search for new Qi-site inhibitors of the bc1 complex.