Chen Hongyi, Mai Ziyun, Jiang Zunyun, Meng Yang, Su Shijun, Wu Lei, Zhang Ming-Zhi, Manahelohe Gizachew Mulugeta, Zhang Weihua, Zhu Yingguang
Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University, 1 Weigang Road, Nanjing, Jiangsu 210095, P. R. China.
Department of Chemistry, College of Natural & Computational Sciences, University of Gondar, Kebele 18, Gondar, Amhara Region 196, Ethiopia.
J Agric Food Chem. 2025 Jul 16;73(28):17994-18002. doi: 10.1021/acs.jafc.5c04753. Epub 2025 Jul 1.
Microtubules are essential components of cells, contributing to the maintenance of cell shape, intracellular transport, cell division, signal transduction, and various other functions. To discover novel tubulin-targeting fungicides, two series of benzimidazole-containing flavonol derivatives were designed, synthesized, and evaluated for their antifungal activity. Compound exhibited optimal antifungal activity against (EC = 0.338 μg/mL), which was superior to those of boscalid (EC = 0.870 μg/mL) and carbendazim (EC = 0.625 μg/mL). experiments demonstrated that compound effectively inhibited infection on tomato fruits at a concentration of 200 μg/mL. Further microscopic observations revealed that compound significantly altered the normal morphology of the mycelia. Immunofluorescence staining experiments revealed that treatment with compound caused significant changes in the structure of intracellular microtubules, consistent with the effects observed for the positive control carbendazim. Moreover, molecular dynamics (MD) simulations, docking experiments, and binding free energy calculations further demonstrated the mechanism of action and binding mode of compound with β-tubulin. The analysis results indicated that compound exhibited a stronger binding affinity for β-tubulin than carbendazim. Ecological and environmental risks of the target compounds were predicted using an online AI-based platform, and the overall profiles indicated a relatively low potential impact. Overall, our study provides a valuable reference for the development of novel tubulin-targeting fungicides.
微管是细胞的重要组成部分，有助于维持细胞形状、细胞内运输、细胞分裂、信号转导及各种其他功能。为了发现新型靶向微管蛋白的杀菌剂，设计、合成了两个系列含苯并咪唑的黄酮醇衍生物，并对其抗真菌活性进行了评估。化合物 对 表现出最佳抗真菌活性（EC = 0.338 μg/mL），优于啶酰菌胺（EC = 0.870 μg/mL）和多菌灵（EC = 0.625 μg/mL）。 实验表明，化合物 在浓度为200 μg/mL时能有效抑制 对番茄果实的感染。进一步的显微镜观察表明，化合物 显著改变了菌丝体的正常形态。免疫荧光染色实验表明，用化合物 处理会导致细胞内微管结构发生显著变化，这与阳性对照多菌灵观察到的效果一致。此外，分子动力学（MD）模拟、对接实验和结合自由能计算进一步证明了化合物 与β-微管蛋白的作用机制和结合模式。分析结果表明，化合物 对β-微管蛋白的结合亲和力比多菌灵更强。使用基于人工智能的在线平台预测了目标化合物的生态和环境风险，总体概况表明潜在影响相对较低。总的来说，我们的研究为新型靶向微管蛋白的杀菌剂的开发提供了有价值的参考。
