Design, Synthesis, and Biological Evaluation of Novel Aryl Sulfonamide Derivatives as Potential Succinate Dehydrogenase Inhibitors Targeting Phytopathogenic Fungi

In our pursuit of novel succinate dehydrogenase inhibitor (SDHI) fungicides for agriculture, we replaced the traditional amide structure with a sulfonamide framework and introduced various heterocyclic and aromatic rings at the sulfonamide's termini. This strategy yielded 30 synthesized compounds, which were screened for antifungal activity against eight phytopathogenic fungi. The biological assay results demonstrated that several target compounds exhibited significant <i>in vitro</i> antifungal activity. Notably, compound <b>2f</b> showed remarkable antifungal activity against <i>Valsa mali</i> with an EC₅₀ value of 0.56 mg/L, outperforming <b>Boscalid</b> (EC₅₀ = 1.79 mg/L). <i>In vivo</i> experiments revealed that compound <b>2f</b> provided significant protection to apple fruits, comparable to <b>Boscalid</b>. SEM analysis of compounds <b>2f</b> and <b>3e</b> showed that compound <b>2f</b> disrupted the structure and morphology of fungal hypha analysis, which suggested that the terminal polyhalogen-substituted pyridine moieties might be pivotal regions influencing their antifungal efficacy. Molecular docking analysis revealed that compound <b>2f</b> and <b>Boscalid</b> exhibited a comparable binding mode to SDH. Furthermore, detailed SDH inhibition assays confirmed the potential of <b>2f</b> (IC₅₀ = 2.51 μM) as prospective SDH inhibitors. RNA transcriptomic analysis indicated that the application of compound <b>2f</b> could influence gene expression in fungi, thereby exerting a defensive effect against plant pathogenic fungi. Consequently, compound <b>2f</b> shows promise for developing a novel and efficient agrochemical fungicide.