Discovery of Novel Diphenyl-Oxime-Ether Derivatives as Potent Succinate Dehydrogenase Inhibitors via Fragment Combination Strategy.

Succinate dehydrogenase inhibitors (SDHIs) have emerged as one of the fastest-growing fungicides, yet their structural conservation and overuse have triggered widespread fungal resistance. Herein, we designed and synthesized a series of novel diphenyl-oxime-ether pyrazole-carboxamide derivatives by employing the fragment combination strategy. Among them, compound 8r exhibited potent SDH inhibition with an IC50 of 0.056 μM, which was approximately a 24-fold improvement over penthiopyrad (IC50 = 1.320 μM). In greenhouse trials, compounds 8t and 8z showed 50% and 40% disease control efficacy against rice sheath blight at 0.78 mg/L, comparable to Thifluzamide (50% control efficacy at 0.78 mg/L). Molecular modeling revealed that halogen substitution enhances intramolecular halogen bonding, stabilizing the cation-π interaction with the C_R46 residue. This work presents a promising scaffold for novel SDHI development.