Design, synthesis, and antifungal activity of licochalcone A derivatives and mechanism of action against Phytopathogenic Fungi.

The exploration of natural products as primary scaffolds remains a valuable strategy for developing novel antifungal agents. Licochalcone A, a bioactive chalcone from licorice, served as a lead for developing novel antifungal agents. This study focused on designing and synthesizing a series of 26 derivatives and subsequently evaluating their antifungal activity against plant pathogens. In vitro antifungal screening against nine fungal strains indicated that most of the compounds demonstrated strong inhibitory activity against Valsa mali. Notably, compound 5b demonstrated significant inhibition against Rhizoctonia solani (IC50 = 3.9 ± 0.2 μg/mL), outperforming the positive control azoxystrobin (29.5 ± 0.3 μg/mL), especially when most other compounds showed little to no activity against this pathogen. Ex vivo assays confirmed that compound 5b provided both protective (76.6% ± 2.6% efficacy) and curative (81.9% ± 4.2% efficacy) effects against R. solani on potato. Mechanistic studies demonstrated that compound 5b severely disrupted fungal hyphal morphology and membrane integrity, as shown by scanning electron microscopy (SEM). Concurrently, catalase (CAT) activity decreased while malondialdehyde (MDA) levels increased. These changes are consistent with the accumulation of intracellular reactive oxygen species (ROS) and the induction of oxidative damage. In conclusion, compound 5b is a promising, multi-target antifungal candidate that acts partly through novel CAT inhibition, providing a new strategy for combating fungal resistance.