Synthesis and Biological Activity of Novel Pyrazol-5-yl-benzamide Derivatives as Potential Succinate Dehydrogenase Inhibitors

Abstract

To promote the discovery and development of new fungicides, a series of novel pyrazol-5-yl-benzamide derivatives were designed, synthesized by hopping and inversion of amide groups of pyrazole-4-carboxamides, and evaluated for their antifungal activities. The bioassay data revealed that compound <b>5IIc</b> exhibited an excellent in vitro activity against <i>Sclerotinia sclerotiorum</i> with an EC₅₀ value of 0.20 mg/L, close to that of commercial fungicide <b>Fluxapyroxad</b> (EC₅₀ = 0.12 mg/L) and <b>Boscalid</b> (EC₅₀ = 0.11 mg/L). For <i>Valsa mali</i>, compound <b>5IIc</b> (EC₅₀ = 3.68 mg/L) showed a significantly higher activity than <b>Fluxapyroxad</b> (EC₅₀ = 12.67 mg/L) and <b>Boscalid</b> (EC₅₀ = 14.83 mg/L). In addition, in vivo experiments proved that compound <b>5IIc</b> has an excellent protective fungicidal activity with an inhibitory rate of 97.1% against <i>S. sclerotiorum</i> at 50 mg/L, while the positive control <b>Fluxapyroxad</b> showed a 98.6% inhibitory effect. The molecular docking simulation revealed that compound <b>5IIc</b> interact with TRP173, SER39, and ARG43 of succinate dehydrogenase (SDH) through a hydrogen bond and p-π interaction, which could explain the probable mechanism of the action between compound <b>5IIc</b> and target protein. Also, the SDH enzymatic inhibition assay was carried out to further validate its mode of action. These results demonstrate that compound <b>5IIc</b> could be a promising fungicide candidate and provide a valuable reference for further investigation.