Potential Succinate Dehydrogenase Inhibitors Bearing a Novel Pyrazole-4-sulfonohydrazide Scaffold: Molecular Design, Antifungal Evaluation, and Action Mechanism.

Aiming to develop novel antifungal agents with a distinctive molecular scaffold targeting succinate dehydrogenase (SDH), 24 '-phenyl-1-pyrazole-4-sulfonohydrazide derivatives were first devised, synthesized, and verified by H NMR, C NMR, high-resolution mass spectrometry (HRMS), and single-crystal X-ray diffraction analysis. The bioassays revealed that the target compounds possessed highly efficient and broad-spectrum antifungal activities against four tested plant pathogenic fungi (), , and . Strikingly, compound was assessed as the selective inhibitor against , with an EC value (0.23 μg/mL) that was similar to that of thifluzamide (0.20 μg/mL). The preventative effect of compound (75.76%) at 200 μg/mL against was roughly comparable to thifluzamide (84.31%) under the same conditions. The exploration of morphological observations indicated that compound could strongly damage the mycelium morphology, obviously increase the permeability of the cell membrane, and dramatically increase the number of mitochondria. Compound also significantly inhibited SDH enzyme activity with an IC value of 0.28 μg/mL, and its fluorescence quenching dynamic curves were similar to that of thifluzamide. Molecular docking and molecular dynamics simulations demonstrated that compound could strongly interact with similar residues around the SDH active pocket as thifluzamide. The present study revealed that the novel '-phenyl-1-pyrazole pyrazole-4-sulfonohydrazide derivatives are worthy of being further investigated as the promising replacements of traditional carboxamide derivatives targeting SDH of fungi.