Design, synthesis, and biological activity studies of formononetin derivatives containing pyrazole amide moieties

BACKGROUND Global food security faces dual challenges from pathogen threats and increasing fungicide resistance, urgently necessitating the development of new pesticides that are efficient, low‐toxicity, and environmentally friendly. Natural products, owing to their structural diversity and environmental compatibility, serve as important resources. Formononetin, a common isoflavone in leguminous plants, exhibits various biological activities. However, its direct antifungal efficacy is limited, leaving potential for structural optimization. RESULTS In this study, 20 formononetin derivatives containing a pyrazole amide moiety were synthesized through structural modification using formononetin as the lead compound. Their antifungal activity against nine plant pathogenic fungi was systematically evaluated. The results showed that most compounds exhibited significant inhibitory effects against Phytophthora capsici ( Pc ), with X5 demonstrating the most potent activity. The EC 50 value of X5 against Pc was 5.2 μg mL −1 , which was significantly lower than those of the positive controls azoxystrobin ( Az , 98.9 μg mL −1 ) and fluopyram ( Fl , 107.2 μg mL −1 ). In vivo experiments further demonstrated that, at a concentration of 200 μg mL −1 , X5 provided 88.7% curative and 85.4% protective efficacy against chili leaf diseases, outperforming Fl (44.9 and 66.5%, respectively). Preliminary insights into its potential mechanism of action were obtained through scanning electron microscopy (SEM), fluorescence microscopy (FM), malondialdehyde (MDA) content measurement, and density functional theory calculations. CONCLUSION Formononetin derivatives containing pyrazole amide structures, which combine high efficiency and multi‐mechanism antifungal activity, demonstrate promising potential for the development of novel plant disease control agents.