Triazole Sulfonamide Derivates: Inhibitors of the <i>bc</i>₁ Complex to Control Cucumber Downy Mildew

Cucumber downy mildew (CDM), caused by <i>Pseudoperonospora cubensis</i>, 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 <i>bc</i>₁ 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 <i>bc</i>₁ complex from <i>P. cubensis</i> 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-<i>bc</i>₁ complex, a scaffold hopping strategy was performed, and compounds <b>11a</b>-<b>o</b> and <b>12a</b>-<b>v</b> were designed. Among them, compound <b>12g</b> 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 <b>12g</b> has the potential to serve as a lead compound in the search for new Qi-site inhibitors of the <i>bc</i>₁ complex.