Plant diseases caused by phytopathogenic fungi are a serious threat in the process of crop production and cause large economic losses to global agriculture. To obtain high-antifungal-activity compounds with novel action mechanisms, a series of 4-substituted mandelic acid derivatives containing a 1,3,4-oxadiazole moiety were designed and synthesized. In vitro bioassay results revealed that some compounds exhibited excellent activity against the tested fungi. Among them, the EC50 values of E13 against Gibberella saubinetii (G. saubinetii), E6 against Verticillium dahlia (V. dahlia), and E18 against Sclerotinia sclerotiorum (S. sclerotiorum) were 20.4, 12.7, and 8.0 mg/L, respectively, which were highly superior to that of the commercialized fungicide mandipropamid. The morphological studies of G. saubinetii with a fluorescence microscope (FM) and scanning electron microscope (SEM) indicated that E13 broke the surface of the hyphae and destroyed cell membrane integrity with increased concentration, thereby inhibiting fungal reproduction. Further cytoplasmic content leakage determination results showed a dramatic increase of the nucleic acid and protein concentrations in mycelia with E13 treatment, which also indicated that the title compound E13 could destroy cell membrane integrity and affect the growth of fungi. These results provide important information for further study of the mechanism of action of mandelic acid derivatives and their structural derivatization.

To investigate the effect of spatial configuration on the biological activity of the compounds, a series of chiral mandelic acid derivatives with a moiety of 1,3,4-oxadiazole thioether have been designed and synthesized. Bioassay results demonstrated that most title compounds with the S-configuration exhibited better in vitro antifungal activity against three plant fungi, such as H3\' (EC50 = 19.3 μg/mL) against Gibberella saubinetii, which was approximately 16 times higher than that of H3 (EC50 = 317.0 μg/mL). CoMFA and CoMSIA models were established for 3D-QSAR analysis and provided an important support for further optimization of this series of compounds. Comparing the preliminary mechanism studies between enantiomers (H3 and H3\') found that the S-configuration compound (H3\') exhibited a stronger ability to destroy the surface structure of G. saubinetii mycelia, causing the leakage of intracellular substances to accelerate and the growth of the hyphae to be inhibited. The results provided a novel view for the further optimization of this series of active compounds and deep mechanism study of chiral pesticides.

Various 1,3,4-oxadiazole thioether 4H-chromen-4-one derivatives were conceived. The title compounds demonstrated striking inhibitory effects against Xac, Psa, and Xoo. EC50 data exhibited that A8 (19.7 μg/mL) had better antibacterial activity against Xoo than myricetin, BT, and TC. Simultaneously, the mechanism of action of A8 had been verified by SEM. The results of anti-tobacco mosaic virus indicated that A9 had the best in vivo antiviral effect compared with ningnanmycin. From the data of MST, it could be seen that A9 (0.003 ± 0.001 μmol/L) exhibited a strong binding capacity, which was far superior to ningnanmycin (2.726 ± 1.301 μmol/L). This study shows that the 1,3,4-oxadiazole thioether 4H-chromen-4-one derivatives may become agricultural drugs with great potential.