Structure-Based Discovery of New Succinate Dehydrogenase Inhibitors via Scaffold Hopping Strategy.

Scaffold hopping strategy has become one of the most successful methods in the process of molecular design. Seeking to develop novel succinate dehydrogenase inhibitors (SDHIs), we employed a scaffold hopping strategy to design compounds featuring geminate dichloralkenes (-dichloralkenes) fragment. After stepwise modifications, a series of -cyclopropyl-dichloralkenes-pyrazole-carboxamide derivatives was synthesized. Among them, compounds (IC = 26.00 nM) and (IC = 27.00 nM) were identified as the best inhibitory activity against porcine SDH, with IC values reaching the nanomolar range, outperforming the lead compound pydiflumetofen. Additionally, the greenhouse assay indicated that compounds (EC = 0.031 mg/L) and (EC = 1.67 mg/L) displayed extremely high activities against wheat powdery mildew (WPM) and cucumber powdery mildew (CPM), respectively. Computational results further revealed that the -dichloralkene fragment and fluorine substituted pyrazole form an extra hydrophobic interaction and dipolar-dipolar interaction with SDH. In summary, our study provides a novel -dichloralkene scaffold with outstanding fungicidal properties, obtained through scaffold hopping, that holds great potential for future research on PM control.