State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry , Nankai University , No. 94, Weijin Road , Tianjin 300071 , P. R. China.
The Ural Federal University Named after the First President of Russia B. N. Yeltsin , 620002 Ekaterinburg , Russia.
J Agric Food Chem. 2019 Nov 27;67(47):13185-13194. doi: 10.1021/acs.jafc.9b05751. Epub 2019 Nov 18.
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 stood out with a broad spectrum of in vitro activity against five fungi. Its EC value (0.73 μg/mL) was comparable to that of boscalid (EC of 0.51 μg/mL) and fluxapyroxad (EC of 0.19 μg/mL) against . For , and with EC values of 4.61 and 6.48 μg/mL, respectively, showed significantly higher activity than fluxapyroxad with the EC value of 16.99 μg/mL. In vivo fungicidal activity of exhibited an excellent inhibitory rate (100%) against at 50 μg/mL, while the positive control boscalid showed only a 70% inhibitory rate. Moreover, showed promising fungicidal activity with a 60% inhibitory rate against at 1 μg/mL, which was better than that of boscalid (30%). Compound possessed better in vivo efficacy against and than boscalid. Molecular docking showed that even the carbonyl oxygen atom of 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 was worthy of further investigation as a promising fungicide candidate.
在寻找新型杀真菌剂先导化合物时，通过羰基和酰胺基团的反转，设计并合成了新型生物活性琥珀酸脱氢酶抑制剂（SDHI）衍生物。生物测定表明，化合物 对五种真菌具有广谱的体外活性，表现突出。其 EC 值（0.73μg/mL）与 boscalid（EC 值为 0.51μg/mL）和 fluxapyroxad（EC 值为 0.19μg/mL）相当，而对 、 、 的 EC 值分别为 4.61μg/mL 和 6.48μg/mL，活性明显高于 EC 值为 16.99μg/mL 的 fluxapyroxad。在 50μg/mL 时，化合物 对 表现出极好的体内杀菌活性（抑制率为 100%），而阳性对照 boscalid 的抑制率仅为 70%。此外，化合物 在 1μg/mL 时对 表现出有希望的杀菌活性，抑制率为 60%，优于 boscalid（30%）。化合物 对 和 具有比 boscalid 更好的体内功效。分子对接表明，即使 中的羰基氧原子远离吡唑环，它也可以与 SDH 上的 TYR58 和 TRP173 的羟基氢和氨基氢分别形成氢键，这与阳性对照 fluxapyroxad 一致。荧光猝灭分析和 SDH 酶抑制研究也验证了其作用模式。我们的研究表明，化合物 值得进一步研究，作为一种有前途的杀菌剂候选物。
