Design, Synthesis and Antifungal Activities of Novel 1,2,4-Oxadiazole Derivatives Containing Piperidine

To search the novel and efficient antifungal lead compounds, seventeen 1,2,4-oxadiazole derivatives 4a similar to 4b and 6a similar to 6o containing piperidine with novel chemical structures were designed and synthesized, which were based on the method of the splicing of bioactive substructures. The structures of target compounds were characterized by H-1 NMR, C-13 NMR and high-resolution mass spectra (HRMS), and the structure of N-(1-benzoylpiperidin-4-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol3-yl)benzamide (6e) was further confirmed by X-ray single crystal diffraction. The bioassay results showed that, at the concentration of 3.13 mg/L, the inhibition rates of N-(1-acetylpiperidin-4-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (6a), N-(1-(cyclopropanecarbonyl)piperidin-4-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (6c), 6e, tert-butyl 4-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)methyl)piperidine-1-carboxylate (4b) and N-((1-benzoylpiperidin4-yl)methyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (6o) against Soybean rust (Phakopsora pachyrhiz) were 70%, 82%, 95%, 78% and 98%, respectively. The above activities were all better than flufenoxadiazam (30%) and control agent difenoconazole (50%). Among them, compounds 6e and 6o could still reach 80% and 75% inhibition rates, respectively at the concentration of 1.56 mg/L. Compounds 6e and 6o also showed prominent antifungal activity against corn rust (Puccinia sorghi), which inhibition rates were 92% and 90%, respectively at the concentration of 0.10 mg/L. The molecular docking simulation revealed that compound 6e has various interactions with histone deacetylase 4 (HDACs 4), and the hydrogen bonding formed with PHE 227 and PHE 226 may be an important reason for the prominent antifungal activity of compound 6e.