Indole-containing acylhydrazone derivatives as antifungal and anti-oomycete agents: synthesis, biological evaluation, and investigation of their potential SDH-targeted mechanism.

The development of highly effective fungicides with low-resistance risk is crucial for crop protection, yield preservation, quality enhancement, and global food security. Driven by this objective, we designed and synthesized 29 heterocyclic indole-containing acylhydrazone derivatives via a systematic optimisation strategy, and the structures of key compound was confirmed by X-ray single-crystal diffraction. Bioevaluation revealed that the optimized Compound A8 exhibited 91.1% in vitro inhibition against P. capsici at 50 μg/mL, outperforming the positive control metalaxyl (88.2%). In vivo assays on pepper plants demonstrated that compound A8 (400 μg/mL) provided 76.0% and 91.1% protection on leaves and fruits, respectively, comparable to that of metalaxyl (89.3% and 87.5%). In addition, compound B2 showed 89.4% inhibition against R. solani at 50 μg/mL, superior to that of fluopyram (43.0%) and fluxapyroxad (88.6%). Morphological observations revealed that compound A8 induced mycelial deformation, fragmentation and retraction, which were consistent with findings from cell membrane permeability and dry weight measurements. Enzyme activity assays and fluorescence quenching studies suggested that succinate dehydrogenase (SDH) is a potential target of A8, which exhibited a mode of action similar to that of the commercial SDHI fluxapyroxad. Furthermore, molecular docking and molecular dynamics (MD) simulations revealed that A8 adopted a binding mode within the SDH active-site pocket that was highly comparable to that of fluxapyroxad. Collectively, these results suggest that heterocyclic indole-containing acylhydrazone derivatives represent promising SDH-targeted inhibitors and provide valuable lead scaffolds for the development of novel SDHIs.