Synthesis and Biological Activity of Novel Succinate Dehydrogenase Inhibitor Derivatives as Potent Fungicide Candidates

Abstract

In searching for novel fungicidal leads, the novel bioactive succinate dehydrogenase inhibitor (SDHI) derivatives were designed and synthesized by the inversion of carbonyl and amide groups. Bioassay indicated that compound <b>5i</b> stood out with a broad spectrum of in vitro activity against five fungi. Its EC₅₀ value (0.73 μg/mL) was comparable to that of boscalid (EC₅₀ of 0.51 μg/mL) and fluxapyroxad (EC₅₀ of 0.19 μg/mL) against <i>Sclerotinia sclerotiorum</i>. For <i>Rhizoctonia cerealis</i>, <b>5i</b> and <b>5p</b> with EC₅₀ values of 4.61 and 6.48 μg/mL, respectively, showed significantly higher activity than fluxapyroxad with the EC₅₀ value of 16.99 μg/mL. In vivo fungicidal activity of <b>5i</b> exhibited an excellent inhibitory rate (100%) against <i>Puccinia sorghi</i> at 50 μg/mL, while the positive control boscalid showed only a 70% inhibitory rate. Moreover, <b>5i</b> showed promising fungicidal activity with a 60% inhibitory rate against <i>Rhizoctonia solani</i> at 1 μg/mL, which was better than that of boscalid (30%). Compound <b>5i</b> possessed better in vivo efficacy against <i>P. sorghi</i> and <i>R. solani</i> than boscalid. Molecular docking showed that even the carbonyl oxygen atom of <b>5i</b> was far from the pyrazole ring. It could also form hydrogen bonds toward the hydroxyl hydrogen and amino hydrogen of TYR58 and TRP173 on SDH, respectively, which consisted of the positive control fluxapyroxad. Fluorescence quenching analysis and SDH enzymatic inhibition studies also validated its mode of action. Our studies showed that <b>5i</b> was worthy of further investigation as a promising fungicide candidate.