Structure-Based Discovery of Trifluoromethyl Oxadiazole Oxime Ethers as Potent Histone Deacetylase Inhibitors

Histone deacetylases (HDACs), well-established epigenetic targets in medicinal chemistry, have recently attracted attention as potential targets for fungicides against phytopathogenic fungi. In this study, EX-3, a known trifluoromethyl oxadiazole (TFMO)-based HDAC inhibitor, was selected as a lead compound. Guided by its binding mode in Pseudomonas aeruginosa HDAC (Pa-HDAC), we designed and synthesized a series of TFMO-oxime ether derivatives. Most derivatives showed potent inhibitory activity against Pa-HDAC. Among them, compound 9q displayed the strongest enzyme inhibition with an IC50 value of 22.9 nM. The cocrystal complex structure of Pa-HDAC-9q revealed a ligand-induced conformational remodeling of Phe343 from a symmetry-related monomer, providing structural insight into the binding mechanism of this series. In greenhouse assays, compound 9b exhibited promising antifungal activity against southern corn rust and soybean rust, with EC50 values of 0.185 mg/L and 0.462 mg/L. These results identify TFMO-oxime ethers as promising scaffolds for HDAC-targeted fungicide discovery.