Novel SDH Inhibitors as Antifungal Leads: From Azobenzene Derivatives to the 1,2,4-Oxadiazole Compounds

Azo-incorporating was reported to be an effective strategy for increasing SDH inhibitory activity but for poor in vivo control effects. Herein, the azo-incorporated compounds were structurally optimized to retain a preferential conformation by replacing the azo bond with their bioisosteres. Interestingly, the 1,2,4-oxadiazole compound <b>D2</b> displayed a broad fungicidal spectrum as well as fluxapyroxad. More excitedly, compound <b>D2</b> showed excellent antifungal activities against rice sheath blight disease both in vitro (EC₅₀ = 0.001 μg/mL) and in vivo (EC₅₀ = 1.08 μg/mL, EC₉₅ = 4.67 μg/mL). In addition, an extra π-π interaction was found between the 1,2,4-oxadiazole ring of compound <b>D2</b> and the phenyl ring of residue D_Y586, which might interpret the enhanced potency of compound <b>D2</b> against <i>Rhizoctonia solani</i>. Further structural optimizations of the 1,2,4-oxadiazole compounds gave several analogues that made a breakthrough in controlling rice blast disease. These 1,2,4-oxadiazole compounds, derived from azobenzene derivatives, could be antifungal leads especially against <i>R. solani</i> and <i>Magnaporthe grisea</i>, exemplifying an interesting mode of pesticide discovery and providing theoretical guidance for innovation of the SDHI fungicide.