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

Abstract

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 (XII6), 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 XII6 has low toxicity. Furthermore, the enzyme activity results showed that compound XII6 is a strong, nonselective HDAC inhibitor. Finally, the structure–activity relationship was established, and the compound XII6-HDAC binding mode was carried out based on the crystal structure of hHDAC1, hHDAC4, and hHDAC6. This work provided an excellent fungicide against rust for further optimization.