Discovery of Novel Natural Maltol-Based Derivatives as Potential Succinate Dehydrogenase Inhibitors

To develop novel fungicidal agents, 40 novel maltol-based derivatives were designed, synthesized, and evaluated for antifungal activity. Most compounds exhibited potent <i>in vitro</i> efficacy against phytopathogenic fungi, with <b>A2</b>, <b>A3</b>, <b>A4</b>, <b>A8</b>, <b>A9</b>, <b>A23</b>, <b>A24</b>, and <b>A25</b> showing strong activity against <i>Rhizoctonia solani</i>. Moreover, compound <b>A2</b> exerted broad-spectrum antifungal effects against six phytopathogenic fungi. <i>In vivo</i> antifungal activities of compound <b>A24</b> against <i>Rhizoctonia solani</i> and <i>Botrytis cinerea</i> highlighted its potential in crop protection. Propidium iodide (PI) staining and cellular content release assays indicated that compound <b>A24</b> disrupted the membrane integrity, thereby inhibiting the mycelial growth and proliferation. Microscopic observations revealed that compound <b>A24</b> caused irregular morphological alterations in the mycelia and cellular structures. Moreover, compound <b>A24</b> induced mitochondrial dysfunction, confirmed by mitochondrial membrane potential (MMP) analysis. Succinate dehydrogenase (SDH) enzyme activity assays and molecular docking studies further demonstrated that compound <b>A24</b> holds considerable promise as a novel SDHI fungicide.