Synthesis and Biological Activity of Novel Pyrazol-5-yl-benzamide Derivatives as Potential Succinate Dehydrogenase Inhibitors.

To promote the discovery and development of new fungicides, a series of novel pyrazol-5-yl-benzamide derivatives were designed, synthesized by hopping and inversion of amide groups of pyrazole-4-carboxamides, and evaluated for their antifungal activities. The bioassay data revealed that compound 5IIc exhibited an excellent in vitro activity against Sclerotinia sclerotiorum with an EC50 value of 0.20 mg/L, close to that of commercial fungicide Fluxapyroxad (EC50 = 0.12 mg/L) and Boscalid (EC50 = 0.11 mg/L). For Valsa mali, compound 5IIc (EC50 = 3.68 mg/L) showed a significantly higher activity than Fluxapyroxad (EC50 = 12.67 mg/L) and Boscalid (EC50 = 14.83 mg/L). In addition, in vivo experiments proved that compound 5IIc has an excellent protective fungicidal activity with an inhibitory rate of 97.1% against S. sclerotiorum at 50 mg/L, while the positive control Fluxapyroxad showed a 98.6% inhibitory effect. The molecular docking simulation revealed that compound 5IIc interact with TRP173, SER39, and ARG43 of succinate dehydrogenase (SDH) through a hydrogen bond and p-π interaction, which could explain the probable mechanism of the action between compound 5IIc and target protein. Also, the SDH enzymatic inhibition assay was carried out to further validate its mode of action. These results demonstrate that compound 5IIc could be a promising fungicide candidate and provide a valuable reference for further investigation.

Bioactivity-Guided Synthesis Accelerates the Discovery of 3-(Iso)quinolinyl-4-chromenones as Potent Fungicide Candidates.

Fungal infections could cause tremendous decreases in crop yield and quality. Natural products, including flavonoids and (iso)quinolines, have always been an important source for lead discovery in medicinal and agricultural chemistry. To promote the discovery and development of new fungicides, a series of 3-(iso)quinolinyl-4-chromenone derivatives was designed and synthesized by the active substructure splicing principle and evaluated for their antifungal activities. The lead optimization was guided by bioactivity. The bioassay data revealed that the 3-quinolinyl-4-chromenone 13 showed significant in vitro activities against S. sclerotiorum, V. mali, and B. cinerea with EC50 values of 3.65, 2.61, and 2.32 mg/L, respectively. The 3-isoquinolinyl-4-chromenone 25 exhibited excellent in vitro activity against S. sclerotiorum with an EC50 value of 1.94 mg/L, close to that of commercial fungicide chlorothalonil (EC50 = 1.57 mg/L) but lower than that of boscalid (EC50 = 0.67 mg/L). For V. mali and B. cinerea, 3-isoquinolinyl-4-chromenone 25 (EC50 = 1.56, 1.54 mg/L) showed significantly higher activities than chlorothalonil (EC50 = 11.24, 2.92 mg/L). In addition, in vivo experiments proved that compounds 13 and 25 have excellent protective fungicidal activities with inhibitory rates of 88.24 and 94.12%, respectively, against B. cinerea at 50 mg/L, while the positive controls chlorothalonil and boscalid showed inhibitory rates of 76.47 and 97.06%, respectively. Physiological and biochemical studies showed that the primary action of mechanism of compounds 13 and 25 on S. sclerotiorum and B. cinerea may involve changing mycelial morphology and increasing cell membrane permeability. In addition, compound 13 may also affect the respiratory metabolism of B. cinerea. This study revealed that compounds 13 and 25 could be promising candidates for the development of novel fungicides in crop protection.