Design, Synthesis, Antifungal Evaluation, and Action Mechanism of Novel <scp>l</scp>-Carvone-Based Derivatives as Potential Succinate Dehydrogenase Inhibitors

Natural products serve as a crucial source of compounds for developing novel agricultural antifungals. In this work, we utilized the natural product l-carvone as a molecular scaffold to design and synthesize three series of novel l-carvone-based derivatives. The <i>in vitro</i> bioassay results indicated that most target compounds exhibited remarkable antifungal activity. Notably, compound <b>C3</b> demonstrated broad-spectrum antifungal activity against <i>Rhizoctonia solani</i>, <i>Botrytis cinerea</i>, <i>Sclerotinia sclerotiorum</i>, <i>Gibberella zeae</i>, and <i>Valsa mali</i>, with EC₅₀ values of 0.274, 0.985, 4.17, 5.71, and 2.29 μg/mL, respectively. The <i>in vivo</i> preventative efficacies of compounds <b>C3</b> and <b>C11</b> against <i>R. solani</i> and of compound <b>C13</b> against <i>B. cinerea</i> revealed that they had potential as novel agricultural antifungals. In the antifungal mechanism study, the cell membrane permeability experiment showed that compound <b>C3</b> significantly increased the permeability of the cell membrane, and microscopic observations revealed that compound <b>C3</b> could significantly destroy the structural integrity of cells and reduce the number of mitochondria, thus affecting the normal growth of mycelia. Furthermore, the mitochondrial membrane potential detection, succinate dehydrogenase (SDH) enzyme assay, molecular dynamics (MD) simulations, and docking experiments further demonstrated that the mechanism of action and binding mode of compound <b>C3</b> with the SDH may be similar to those of thifluzamide. The abovementioned results provided a valuable reference for the discovery of novel SDH inhibitor fungicides.