Discovery, Optimization, and Biological Evaluation of Novel Pyrazol-5-yl-phenoxybenzamide Derivatives as Potent Succinate Dehydrogenase Inhibitors.

The diphenyl ether molecular pharmacophore has played a significant role in the development of fungicidal compounds. In this study, a variety of pyrazol-5-yl-phenoxybenzamide derivatives were synthesized and evaluated for their potential to act as succinate dehydrogenase inhibitors (SDHIs). The bioassay results indicate certain compounds to display a remarkable and broad-spectrum in their antifungal activities. Notably, compound exhibited significant activities against , , and , with EC values of 0.52, 1.46, and 3.42 mg/L, respectively. These values were lower or comparable to those of (EC = 12.5, 1.93, and 8.33 mg/L, respectively). Additionally, compound showed promising antifungal activities against (EC = 0.82 mg/L) and (EC = 1.86 mg/L), albeit lower than (EC = 0.23 and 0.62 mg/L). Further experiments demonstrated compound to possess effective protective antifungal activities against and at a concentration of 100 mg/L, with inhibition rates of 66.7 and 89.3%, respectively. In comparison, showed inhibition rates of 29.2 and 96.4% against and , respectively. Molecular docking analysis revealed that compound interacts with SDH through hydrogen bonding, π-cation, and π-π interactions, providing insights into the probable mechanism of action. Furthermore, compound exhibited greater binding energy and SDH enzyme inhibitory activity than (Δcal = -46.8 kcal/mol, IC = 1.22 mg/L, compared to Δcal = -41.1 kcal/mol, IC = 8.32 mg/L). Collectively, our results suggest that compound could serve as a promising fungicidal lead compound for the development of more potent SDHIs for crop protection.