Novel 5-(Trifluoromethyl)-1,2,4-oxadiazole-Based Pyrimidin-4-ether Histone Deacetylase Inhibitors for Controlling Rust Disease: Design, Synthesis, Activity, and Structure–Activity Relationship

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 <i>Puccinia sorghi</i>, <i>Phakopsora pachyrhizi</i>, and <i>Puccinia rubigo</i>. 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 <i>P. pachyrhizi</i> 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 <i>P. rubigo</i> 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.