Songtao Liu, Wanting Zhang, Xiyuan Zhu, Ziyang Yang, Shuai Yang, Linwei Li, Lianshan Li, Hong Zhu, Renkai Lei, Yulan Liu, Yiming Geng, Xinyan Chu, Wangyang Li, Shu Xu, Bo Ouyang, Bi Wang, Wei Song, Yu Chen, Xu Feng, Jiaxing Yan, Fei Liu, Feng Zhang
Fusarium head blight (FHB) is a devastating wheat disease causing yield losses and mycotoxin contamination. Phenamacril, a myosin I-targeting fungicide, has a limited antifungal spectrum. Using structure-based drug design focusing on M375 in Fusarium graminearum myosin I (FgMyoI), we synthesized 25 phenamacril derivatives. The II-2 emerged as the most potent inhibitor (EC50 = 0.0077 mg/L against F. graminearum), with broad-spectrum activity against various phytopathogens. Biochemical and computational analyses confirmed that II-2 tightly binds FgMyoI and inhibits its ATPase activity. In vivo tests demonstrated excellent protective and curative efficacy against FHB in wheat and corn, while toxicity assays revealed low risk to nontarget organisms. These results identify II-2 as a promising myosin inhibitor and a novel candidate for FHB management. This work also provides a foundation for the rational design of myosin-targeting fungicides against diverse plant fungal diseases.