Succinate-ubiquinone oxidoreductase (SQR, EC 1.3.5.1, respiratory complex II) has been demonstrated as a promising target for numerous agricultural fungicides. With the aim to identify new lead structures, a novel scaffold of SQR-inhibiting compounds was discovered from the natural product sclerotiorin for the first time. Bioassays suggested variable inhibitory activities of these compounds against succinate-cytochrome reductase [SCR, a mixture of SQR and the bc1 complex (respiratory complex III)]. Notably, compound 2m, which bears a 4-ethoxy phenyl group on the C-5 position and a phenyl motif on the C-3 position of sclerotiorin, showed excellent inhibition potency with an IC50 value of 2.27 μM, demonstrating comparable potency to the commercial control penthiopyrad. Further experiments inferred that these newly prepared compounds exclusively inhibited the activity of SQR. Finally, the in vivo antifungal activities of selected compounds were evaluated. The results indicated that most of the tested compounds showed a broad spectrum of antifungal activities. In particular, compound 2f exhibited antifungal activities against all the seven tested fungal pathogens. Thus, the 3,5-diaryl substituted sclerotiorin was demonstrated as a totally novel promising skeleton for discovering SQR-inhibiting fungicides.
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