Design, Synthesis, and Fungicidal Evaluation of Novel 1,3-Benzodioxole-Pyrimidine Derivatives as Potential Succinate Dehydrogenase Inhibitors

A series of novel 1,3-benzodioxole-pyrimidine derivatives were designed and synthesized. The in vitro bioassay indicated that compounds 4e, 4g, 4n, 5c, and 5e displayed excellent fungicidal activities against test fungal strains. Especially, in the in vitro experiments, 5c exhibited a broad spectrum of fungicidal activity against Botrytis cinerea, Rhizoctonia solani, Fusarium oxysporum, Alternaria solani, and Gibberella zeae with EC50 values of 0.44, 6.96, 6.99, 0.07, and 0.57 mg/L, respectively, which were significantly more potent than those of positive control boscalid (EC50: 5.02, >50, >50, 0.16, and 1.28 mg/L). In vivo testing on tomato fruits and leaves showed that 5c displayed considerable protective and curative efficacy against A. solani. Scanning electron microscopy analysis indicated that 5c possessed a strong ability to destroy the surface morphology of mycelia and seriously interfere with the growth of the fungal pathogen. In the in vitro enzyme inhibition assay, 5c exhibited pronounced succinate dehydrogenase (SDH) inhibitory activity with an IC50 value of 3.41 μM, equivalent to that of boscalid (IC50: 3.40 μM). In addition, fluorescence quenching experiment further confirmed the strong interaction of 5c with SDH. Through chiral resolution, 5c was separated into two enantiomers. Among them, (S)-5c exhibited stronger fungicidal activity (EC50: 0.06 mg/L) and SDH inhibitory (2.92 μM) activity than the R-enantiomer (EC50: 0.17 mg/L and SDH IC50: 3.68 μM), which was in accordance with the molecular docking study (CDOCKER Interaction Energy for (R)-5c and (S)-5c: -28.23 and -29.98 kcal/mol, respectively). These results presented a promising lead for the discovery of novel SDHIs as antifungal pesticides.