Novel Camphor Sulfonohydrazide and Sulfonamide Derivatives as Potential Succinate Dehydrogenase Inhibitors against Phytopathogenic Fungi/Oomycetes

To discover novel fungicidal agrochemicals for treating wheat scab, 39 novel camphor sulfonohydrazide/sulfonamide derivatives 4a-4t and 6a-6s were designed and synthesized. In the in vitro antifungal/antioomycete assay, compounds 4g, 4n, and 4o displayed significant inhibitory activities against Fusarium graminearum, Botryosphaeria dothidea, and Phytophthora capsici. Among them, 4n exhibited the best antifungal activity against F. graminearum with an EC50 value of 0.41 mg/L, which was at the same level as that of pydiflumetofen. The in vivo experiment revealed that 4n presented excellent protective and curative efficacy toward F. graminearum. In the antifungal mechanism study, 4n could increase the cell membrane permeability and reduce the exopolysaccharide and ergosterol content of F. graminearum. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses revealed that 4n could significantly damage the surface morphology and the cell ultrastructure of mycelia to interfere with the growth of F. graminearum. Furthermore, 4n exhibited potent succinate dehydrogenase (SDH) inhibitory activity in vitro with an IC50 value of 3.94 μM, which was equipotent to pydiflumetofen (IC50 = 4.07 μM). The molecular dynamics simulation and docking study suggested that compound 4n could well occupy the active site and form strong interactions with the key residues of SDH. The above-mentioned results demonstrated that the title camphor sulfonohydrazide/sulfonamide derivatives could be promising lead compounds for further succinate dehydrogenase inhibitor (SDHI) fungicide development.