Novel 5‑(Trifluoromethyl)-1,2,4-oxadiazole-BasedPyrimidin-4-ether Histone Deacetylase Inhibitors for Controlling RustDisease: Design, Synthesis, Activity, and Structure–ActivityRelationship

Rust disease, an important plant pathogen, can lead to reduced crop or fruit production. Trifluoromethyloxadiazole (TFMO) is a class of histone deacetylase inhibitors (HDACs). Herein, a series of 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO)-based pyrimidin-4-ether derivatives were designed and synthesized. Antirust bioassay results of TFMOs showed that some of them possessed excellent activities against plant rust pathogens, such as Puccinia sorghi, Phakopsora pachyrhizi, and Puccinia rubigo. The most active compound, 3-(5-(((6-(difluoromethyl)pyrimidin-4-yl)oxy)methyl)thiophen-2-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (<b>XII6</b>), exhibited 50% control against P. pachyrhizi at 0.780 mg/L, which was significantly better than the commercial fungicide azoxystrobin (0%) at the same concentration. The field trial results indicated that the compound exhibited an excellent control effect against P. rubigo at 116 g a.i./ha. The acute toxic results indicated that compound <b>XII6</b> has low toxicity. Furthermore, the enzyme activity results showed that compound <b>XII6</b> is a strong, nonselective HDAC inhibitor. Finally, the structure–activity relationship was established, and the compound <b>XII6</b>-HDAC binding mode was carried out based on the crystal structure of <i>h</i>HDAC1, <i>h</i>HDAC4, and <i>h</i>HDAC6. This work provided an excellent fungicide against rust for further optimization.