Synthesis, Antifungal Activity, and Molecular Simulation of Vanillin-Based 1,3,4-Oxadiazole-Thioether Derivatives as Potential Succinate Dehydrogenase Inhibitors

To explore potent natural product-based antifungal agents, thirty-two new vanillin-based 1,3,4-oxadiazole-thioether compounds were rationally designed and synthesized in this study. Their chemical structures were comprehensively confirmed by FT-IR, 1H NMR, 13C NMR, and HRMS. The in vitro antifungal activity of the target compounds against eight phytopathogenic fungi was preliminarily assayed using the agar dilution method, with the commercial fungicide boscalid, a succinate dehydrogenase inhibitor (SDHI), as the positive control. Results indicated that compounds 6n, 6o, and 6r displayed significant inhibitory activity against Physalospora piricola (P. p.). Further EC50 tests revealed that these three compounds were all more effective than boscalid. Subsequently, to explore the relationship between structures of the target compounds and their antifungal activity against P. p., a valid and reliable three-dimensional quantitative structure–activity relationship (3D-QSAR) model was established via the CoMFA method. Also, the density functional theory (DFT) calculations, including ESP and FMOs, were calculated to further elucidate the structure–activity relationship. To investigate the action mechanism between the target compounds and the potential biological target succinate dehydrogenase (SDH), the inhibitory activity of compounds 6n, 6o, and 6r against SDH was assessed in this work. The results displayed that their SDH inhibitory activities were superior to that of the positive control, boscalid. Molecular docking simulations revealed that compound 6n exhibited a binding mode similar to that of boscalid. Therefore, the target compound 6n might exert excellent antifungal activity through inhibition of SDH. Compound 6n deserves in-depth research as a lead compound for developing novel fungicides.