Rational Design, Synthesis, and Biological Evaluation of Fluorine- and Chlorine-Substituted Pyrazol-5-yl-benzamide Derivatives as Potential Succinate Dehydrogenase Inhibitors

Abstract

To develop novel succinate dehydrogenase inhibitors (SDHIs), two series of novel <i>N</i>-4-fluoro-pyrazol-5-yl-benzamide and <i>N</i>-4-chloro-pyrazol-5-yl-benzamide derivatives were designed and synthesized, and their antifungal activities were evaluated against <i>Valsa mali</i>, <i>Sclerotinia sclerotiorum</i>, <i><i>FusaHum graminearum</i> Sehw</i>, <i>Physalospora piricola</i>, and <i>Botrytis cinerea</i>. The bioassay results showed that some of the target compounds exhibited good antifungal activities <i>in vitro</i> against <i>V. mali</i> and <i>S. sclerotiorum</i>. Remarkably, compound <b>9Ip</b> displayed good <i>in vitro</i> activity against <i>V. mali</i> with an EC₅₀ value of 0.58 mg/L. This outcome was 21-fold greater than that of <b>fluxapyroxad</b> (12.45 mg/L) and close to that of the commercial fungicide <b>tebuconazole</b> (EC₅₀ = 0.36 mg/L). In addition, <i>in viv</i>o experiments proved that compound <b>9Ip</b> has good protective fungicidal activity with an inhibitory rate of 93.2% against <i>V. mali</i> at 50 mg/L, which was equivalent to that of the positive control <b>tebuconazole</b> (95.5%). The results of molecular docking indicated that there were obvious hydrogen bonds and p-π interactions between compound <b>9Ip</b> and succinate dehydrogenase (SDH), which could explain the probable action mechanism. In addition, the SDH enzymatic inhibition assay was carried out to further prove its mode of action. Our studies suggest that compound <b>9Ip</b> could be a fungicidal lead to discover more potent SDHIs for crop protection.