Design, Synthesis, and Biological Evaluation of Novel Camphor-Based Hydrazide and Sulfonamide Derivatives as Laccase Inhibitors against Plant Pathogenic Fungi/Oomycetes.

To discover novel natural product-based fungicidal agrochemicals, 41 novel camphanic acid hydrazide and camphor sulfonamide derivatives were designed, synthesized, and tested for their antifungal profile against four plant pathogenic fungi and three oomycetes. As a result, some derivatives presented pronounced inhibitory activities toward , , , and . Especially, compound demonstrated the most potent anti- activity (EC = 1.28 mg/L), much stronger than positive control chlorthalonil. The assay showed that displayed significant protective and curative effects on apple fruits infected by . The primary antifungal mechanism study revealed that could obviously enhance the cell membrane permeability, destroy the mycelial surface morphology and the cell ultrastructure, and reduce the ergosterol and exopolysaccharide contents of . Further, showed potent laccase inhibitory activity with an IC value of 11.3 μM, superior to positive control cysteine. The molecular docking study revealed that could dock well into the active site of laccase by forming multiple interactions with the key residues in the pocket. The acute oral toxicity test in rats presented that had slight toxicity with an LD value of 849.1 mg/kg bw (95% confidence limit: 403.9-1785.3 mg/kg bw). This research identified that the camphanic acid hydrazide derivatives could be promising leads for the development of novel laccase-targeting fungicides.