Design and Synthesis of Novel Diphenyl Ether Carboxamide Derivatives To Control the Phytopathogenic Fungus <i>Sclerotinia sclerotiorum</i>

Abstract

Sclerotinia stem rot (SSR) caused by the phytopathogenic fungus <i>Sclerotinia sclerotiorum</i> has led to serious losses in the yields of oilseed rape and other crops every year. Here, we designed and synthesized a series of carboxamide derivatives containing a diphenyl ether skeleton by adopting the scaffold splicing strategy. From the results of the mycelium growth inhibition experiment, inhibition rates of compounds <b>4j</b> and <b>4i</b> showed more than 80% to control <i>S. sclerotiorum</i> at a dose of 50 μg/mL, which is close to that of the positive control (flubeneteram, 95%). Then, the results of a structure-activity relationship study showed that the benzyl scaffold was very important for antifungal activity and that introducing a halogen atom on the benzyl ring would improve antifungal activity. Furthermore, the results of an in vitro activity test suggested that these novel compounds can inhibit the activity of succinate dehydrogenase (SDH), and the binding mode of <b>4j</b> with SDH was basically similar to that of the flutolanil derivative. Morphological observation of mycelium revealed that compound <b>4j</b> could cause a damage on the mycelial morphology and cell structure of <i>S. sclerotiorum</i>, resulting in inhibition of the growth of mycelia. Furthermore, in vivo antifungal activity assessment of <b>4j</b> displayed a good control of <i>S. sclerotiorum</i> (>97%) with a result similar to that of the positive control at a concentration of 200 mg/L. Thus, the diphenyl ether carboxamide skeleton is a new starting point for the discovery of new SDH inhibitors and is worthy of further development.