Design, synthesis, antifungal evaluation and mechanism study of novel thiazolamide derivatives containing a diarylamine scaffold.

Succinate dehydrogenase (SDH), cellular respiratory chain, and tricarboxylic acid (or Krebs cycle) have been identified as one of the most important targets for pharmaceuticals and agricultural chemicals. However, due to the serious resistance issues faced by these fungicides, it is necessary to continuously develop new fungicides to overcome resistance problems. Herein, a series of novel thiazolamide derivatives containing a diarylamine scaffold were designed, synthesized, and evaluated for their antifungal activities against four fungi (Rhizoctonia solani, Sclerotinia sclerotiorum, Alternaria alternata, and Alternaria solani). The antifungal bioassay identified compound 7p as a highly active agent, exhibiting anti-R. solani activity comparable to that of the marketed fungicide thifluzamide. In addition, cytotoxicity tests showed that compound 7p had the advantage of lower toxicity than thifluzamide, which had the potential to be developed as a green fungicide. A series of mechanistic evaluations-including SDH inhibition assays, mycelial respiration inhibition tests, assessments of mitochondrial membrane potential, molecular docking, determination of cell membrane permeability and cytoplasmic content leakage, and morphological analysis using fluorescence microscopy and scanning electron microscopy-indicated that the site of action of compound 7p extended beyond SDH; it also exerted a significant damaging effect on the fungal mycelial cell membrane. The results of the present work provided valuable insights for the development of novel fungicides aimed at addressing resistance to SDH inhibitors.