Molecular Concatenation of 3,5-Dichloro-2,6-Difluoropyridin-4-amine with Heterocyclic Carboxylic Acids and Evaluation of their Antifungal Activity

Succinate dehydrogenase (SDH) inhibitors face cross-resistance issues due to similar structures. To address this problem, we designed heterocyclic carboxamide derivatives based on a 3,5-dichloro-2,6-difluoropyridin-4-amine scaffold. Compounds A1 and A2 showed excellent antifungal activity against Rhizoctonia solani (EC 50 = 1.08 and 1.18 mg/L), outperforming boscalid (EC 50 = 1.82 mg/L). They also exhibited broad-spectrum activity against four pathogenic fungi. In vivo rice leaf tests confirmed good protective effects ( A1 and A2 at 92.88% and 89.35%, respectively). Mechanistic studies revealed that A1 and A2 disrupt mycelial morphology (Scanning electron microscopy analysis and transmission electron microscopy analysis) and inhibit SDH, supported by molecular docking and enzyme activity assays. Importantly, acute oral toxicity to bees was low (LC 50 > 500 mg/L), comparable to commercial fungicides. These results identify A1 and A2 as promising, bee-safe leads for next-generation SDHI fungicides.