Abstract BACKGROUND Asian soybean rust caused by Phakopsora pachyrhizi ( P. pachyrhizi ) poses a serious threat to global soybean production, and resistance to conventional fungicides is increasing. Therefore, new fungicides with novel modes of action are urgently needed. This study aimed to design and optimize potent 5‐(trifluoromethyl)‐1,2,4‐oxadiazole (TFMO) derivatives inspired by fungal histone deacetylase inhibition. RESULTS Forty‐two TFMO derivatives were synthesized through bioisosteric modification and linker optimization. Among them, FM‐17888 showed the highest activity against P. pachyrhizi , with an EC 50 value of 0.0583 mg·L −1 , approximately eightfold lower than that of flufenoxadiazam. Under the tested greenhouse conditions, FM‐17888 also showed good crop safety and selective activity against Puccinia triticina . Molecular docking and DFT analyses suggested that its improved activity may be associated with favorable binding geometry, additional π ‐sulfur interactions, and a reduced HOMO‐LUMO energy gap. CONCLUSION FM‐17888 is a potent and selective TFMO lead compound for soybean rust control. Together with the greenhouse bioassay, docking, and DFT results, these findings support FM‐17888 as a promising candidate for further development against rust diseases, while direct target‐validation studies are still needed to confirm its precise mode of action. © 2026 Society of Chemical Industry.
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