Design, synthesis, antifungal evaluation and mechanism study of novel norbornene derivatives as potential laccase inhibitors

BACKGROUND

To discover novel fungicide candidates, five series of novel norbornene hydrazide, bishydrazide, oxadiazole, carboxamide and acylthiourea derivatives (2a‐2 t, 3a‐3 f, 4a‐4 f, 5a‐5 f and 7a‐7 f) were designed, synthesized and assayed for their antifungal activity toward seven representative plant fungal pathogens.

RESULTS

In the in vitro antifungal assay, some title norbornene derivatives presented good antifungal activity against Botryosphaeria dothidea, Sclerotinia sclerotiorum and Fusarium graminearum. Especially, compound 2b exhibited the best inhibitory activity toward B. dothidea with the median effective concentration (EC₅₀) of 0.17 mg/L, substantially stronger than those of the reference fungicides boscalid and carbendazim. The in vivo antifungal assay on apples revealed that 2b had significant curative and protective effects, both of which were superior to boscalid. In the preliminary antifungal mechanism study, 2b was able to injure the surface morphology of hyphae, destroy the cell membrane integrity and increase the intracellular reactive oxygen species (ROS) level of B. dothidea. In addition, 2b could considerably inhibit the laccase activity with the median inhibitory concentration (IC₅₀) of 1.02 μM, much stronger than that of positive control cysteine (IC₅₀ = 35.50 μM). The binding affinity and interaction mode of 2b with laccase were also confirmed by molecular docking.

CONCLUSION

This study presented a promising lead compound for the study on novel laccase inhibitors as fungicidal agrochemicals, which demonstrate significant anti‐B. dothidea activity and laccase inhibitory activity.

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