Designing dual-active fungicides for simultaneous inhibition of multiple target sites

The repeated application of fungicides with different modes of action is indispensable in current disease management programs to effectively control diseases and to delay the development of resistance in fungal plant pathogens. Fungicides can be applied in alternation or together in a mixture, the latter can be developed by a manufacturer as a co-formulation or prepared by the user as a tank mix. Although there are numerous advantages of using fungicide mixtures, their preparation requires more expert knowledge about the composition of single components and their incompatibility may lead to the loss of their efficacy. To avoid these drawbacks, our aim was to combine two fungicides with different modes of action into a single molecule, preserving its dual activity against both molecular targets of single fungicides. In particular, we covalently joined the pharmacophores of strobilurin- and succinate dehydrogenase inhibitor (SDHI) fungicides with a linker to obtain novel hybrid molecules. The compounds were tested against important fungal plant pathogens and showed good inhibition of Pyricularia oryzae and Sclerotinia sclerotiorum with activity comparable to commercial fungicides. The inhibition of the cytochrome bc1 and the succinate dehydrogenase enzyme activities confirmed dual mechanism of action of the new molecules. The dual-active molecules will be further optimized to increase their binding and inhibition of the two targets.