BACKGROUNDThe development of fungicides with low cross resistance, high efficacy and low resistance plays a central role in protecting crops, reducing yield losses, improving quality and maintaining global food security. Based on this important role, after a systematic optimization strategy, novel heterocyclic amide derivatives bearing diphenylmethyl fragment were screened, synthesized and verified with the spectrographic and x‐ray diffraction analysis.RESULTSIn this study, the aforementioned optimization obtained compound B19 that was measured for antifungal activity against Rhizoctonia solani (median effective concentration, EC50 = 1.11 μg mL−1). Meanwhile, the anti‐R. solani protective effect (79.34%) of compound B19 was evaluated in vivo at 100 μg mL−1, which is comparable to that of the control agent fluxapyroxad (80.67%). Thence, morphological observations revealed that compound B19 induced mycelium disruption and shrinking, mitochondrial number reduction and apoptosis acceleration, consistent with the results of the mitochondrial membrane potential and cell membrane permeability. Further investigations found that the potential target enzyme of compound B19 was SDH, which exerted fluorescence quenching dynamic curves similar to that of the commercialized SDHI fluxapyroxad. Additionally, research by molecular docking and MD simulations demonstrated that compound B19 had a similar binding mode acting on the surrounding residues in the SDH active pocket to that offluxapyroxad.CONCLUSIONThe above results demonstrated that heterocyclic amide derivatives containing a diphenylmethyl moiety are promising scaffolds for targeting SDH of fungi and provide valuable antifungal leads with the potential to develop new SDH inhibitors. © 2024 Society of Chemical Industry.

中文翻译：

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含有二苯甲基部分的新型杂环酰胺衍生物：系统优化、合成、抗真菌活性和作用机制


背景技术开发低交叉抗性、高效低抗性的杀菌剂对于保护作物、减少产量损失、提高品质和维护全球粮食安全具有重要作用。基于这一重要作用，经过系统的优化策略，筛选、合成了带有二苯甲基片段的新型杂环酰胺衍生物，并通过光谱和X射线衍射分析进行了验证。 结果在本研究中，上述优化得到了化合物B19，并对其抗真菌活性进行了测定。对立枯丝核菌的活性（中位有效浓度，EC50 = 1.11 μg mL−1）。与此同时，抗R。在体内评估化合物 B19 在 100 μg mL−1 浓度下的茄病保护作用 (79.34%)，与对照剂 Fluxapyroxad 的保护作用 (80.67%) 相当。因此，形态学观察表明，化合物B19诱导菌丝破坏和收缩、线粒体数量减少和细胞凋亡加速，与线粒体膜电位和细胞膜通透性的结果一致。进一步研究发现，化合物B19的潜在靶酶是SDH，其荧光猝灭动态曲线与商品化的SDHI Fluxapyroxad相似。此外，分子对接和MD模拟研究表明，化合物B19对SDH活性口袋周围残基的作用与offluxapyroxad具有相似的结合模式。结论上述结果表明，含有二苯甲基部分的杂环酰胺衍生物是靶向SDH的有前途的支架真菌并提供有价值的抗真菌线索，具有开发新 SDH 抑制剂的潜力。 © 2024 化学工业协会。