Novel Diphenyl Ether Carbonyl Ester Fragment as a Promising Skeleton Targeting Succinate Dehydrogenase

Succinate dehydrogenase (SDH) is a globally recognized critical target for fungicides. Our research mainly focuses on discovering novel molecular skeletons targeting SDH. We designed a series of diphenyl ether ester derivatives that exhibit potential efficacy against <i>Rhizoctonia solani</i> by utilizing a bioisosteric approach. These results indicate that compounds with shorter linkers significantly enhance the antifungal activity. Furthermore, the antifungal potential of an ester-linked compound was superior to its amide and <i>N</i>-(alkoxy) counterparts. Specifically, compound <b>ba</b> achieved a remarkable 92% efficacy in controlling <i>R. solani</i> at a dosage of 50 μg/mL with an EC₅₀ value of 0.44 μg/mL, thus outperforming boscalid without negatively impacting rice growth. Moreover, <b>ba</b> caused significant damage to the <i>R. solani</i> mycelium and demonstrated an IC₅₀ value of 1.69 μM against <i>R. solani</i> SDH, exhibiting efficacy comparable to that of boscalid. These results unveil a promising avenue for replacing traditional heterocyclic amide-based inhibitors, potentially heralding a new generation of SDH-targeting fungicides.