To search the novel and efficient antifungal lead compounds, seventeen 1,2,4-oxadiazole derivatives 4a~4b and 6a~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 ¹H NMR, ¹³C NMR and high-resolution mass spectra (HRMS), and the structure of N-(1-benzoylpiperidin-4-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadia- zol-3-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-benzoyl- piperidin-4-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.

Key words: piperidine, 1,2,4-oxadiazole, synthesis, antifungal activity, molecular docking