Chelation of the Optimal Antifungal Pogostone Analogue with Copper(II) to Explore the Dual Antifungal and Antibacterial Agent

In an ongoing effort to explore more potent antifungal pogostone (Po) analogues, we maintained the previously identified 3-acetyl-4-hydroxy-2-pyrone core motif while synthesizing a series of Po analogues with variations in the alkyl side chain. The in vitrobioassay results revealed that compound 21was the most potent antifungal analogue with an EC50value of 1.1 μg/mL against Sclerotinia sclerotiorum(Lib.) de Bary. Meanwhile, its Cu(II) complex 34manifested significantly enhanced antibacterial activity against Xanthomonas campestris pv campestris(Xcc) with a minimum inhibitory concentration (MIC) value of 300 μg/mL compared with 21(MIC = 700 μg/mL). Complex 34exhibited a striking preventive effect against S. sclerotiorumand Xccin rape leaves, with control efficacies of 98.8% (50 μg/mL) and 80.7% (1000 μg/mL), respectively. The 3D-QSAR models generated using Topomer comparative molecular field analysis indicated that a shorter alkyl chain (carbon atom number <8), terminal rings, or electron-deficient groups on the alkyl side chain are beneficial for antifungal potency. Further, bioassay results revealed that the component of 21in complex 34dominated the antifungal activity, but the introduction of Cu(II) significantly enhanced its antibacterial activity. The toxicological observations demonstrated that 21could induce abnormal mitochondrial morphology, loss of mitochondrial membrane potential, and reactive oxygen species (ROS) accumulation in S. sclerotiorum. The enzyme assay results showed that 21is a moderate promiscuous inhibitor of mitochondrial complexes II and III. Besides, the introduction of Cu(II) to 34could promote the disruption of the cell membrane and intracellular proteins and the ROS level in Xcccompared with 21. In summary, these results highlight the potential of 34as a dual antifungal and antibacterial biocide for controlling rape diseases or as a promising candidate for further optimization.