Design, Synthesis, Antifungal Activity, and Molecular Docking Studies of Novel Chiral Isoxazoline-Benzofuran-Sulfonamide Derivatives

Abstract

Succinate dehydrogenase (SDH) is one of the most important molecular targets for the development of novel fungicides. With the emerging problem of resistance in plant fungal pathogens, novel compounds with high fungicidal activity need to be developed, but the study of chiral pesticides for the inhibition of highly destructive plant pathogens has been rarely reported in recent years. Therefore, a series of novel chiral isoxazoline-benzofuran-sulfonamide derivatives were designed to investigate potential novel antifungal molecules. The chiral target compound <b>3a</b> was cultured as a single crystal and confirmed using X-ray diffraction. All the target compounds were tested for antifungal activity, and compounds <b>3c</b>, <b>3i</b>, <b>3s</b>, and <b>3r</b> were found to have significant antifungal effects against <i>S. sclerotiorum</i> with EC₅₀ values of 0.42 mg/L, 0.33 mg/L, 0.37 mg/L, and 0.40 mg/L, respectively, which were superior to the commercial fungicide fluopyram (EC₅₀ = 0.47 mg/L). The IC₅₀ value of compound <b>3i</b> against the SDH of <i>S. sclerotiorum</i> was 0.63 mg/mL, which was further demonstrated by enzyme activity assays. Scanning electron microscopy showed that <b>3i</b> had a significant inhibitory effect on <i>S. sclerotiorum</i>. In addition, the fluorescence quenching analysis assay indicated that compound <b>3i</b> had a similar effect with the positive control fluopyram. Molecular docking exhibited that target compounds with chiral configuration had better affinity than racemic configuration, and <b>3i</b> possessed stronger action than fluopyram, which was in keeping with the <i>in vitro</i> test results. These results would provide a basis and reference for the development of novel chiral fungicides.