Discovery of novel phenamacril-diphenyl ether hybrids as antifungal leads with a low-toxicity profile.
TL;DR
This research provides novel insights for the development of highly active and low-toxic phenamacril derivatives, and lays the foundation for achieving a closed-loop research and development process involving structure-activity relationships, toxicity prediction, iterative optimization, and re-evaluation.
Abstract
Background
Fusarium head blight (FHB) is a devastating disease affecting cereal crops, directly causing yield losses and the production of harmful mycotoxins. Phenamacril is a highly effective, low-toxicity, environmentally friendly fungicide with high species specificity for controlling FHB. Based on this, novel phenamacril derivatives containing a diphenyl ether moiety were designed and synthesized according to the active substructure splicing principle.
Results
In vitro antifungal assays revealed that compounds A1 and A3 exhibited significant inhibitory activity against Fusarium graminearum, with compound A3 demonstrating the strongest effect. At a concentration of 50 μg/mL, it achieved an inhibition rate of 98.06% with a half-maximal effective concentration (EC50) of 2.41 μg/mL. Molecular docking revealed that compound A3 could bind to the target protein Myosin-5 in a manner similar to phenamacril. To further assess the toxicity of the target compounds, five fluorescence spectral parameters were used in the toxicity prediction model, and the calculated median lethal dose (LD50) of compound A3 was 4920.147 mg/kg. The results demonstrated that compound A3 has the same low-toxicity characteristic as phenamacril, which provides a core foundation for subsequent structural optimization.
Conclusion
This research provides novel insights for the development of highly active and low-toxic phenamacril derivatives, and lays the foundation for achieving a closed-loop research and development process involving structure-activity relationships, toxicity prediction, iterative optimization, and re-evaluation. © 2026 Society of Chemical Industry.