Evaluation of natural l‐phenylalanine‐derived Amidohydrazide derivatives in ensuring agriculture production against phytopathogenic fungi†

Abstract BACKGROUND Ensuring food security is fundamental to national security and an important guarantee for global peace and development. The use of fungicides represents an effective strategy in safeguarding sufficient food supply against phytopathogenic fungi; however, given the escalating pathogen resistance, there is an urgent need to develop new, highly efficient, and environmentally friendly green fungicides. RESULTS In this study, 24 novel amidohydrazide derivatives were designed and synthesized by incorporating the bioactive amide and hydrazide groups into natural l ‐phenylalanine. The bioassays revealed that certain compounds exhibited remarkable inhibitory activity against agricultural pathogenic fungi, with compound A21 particularly displaying exceptional in vitro and in vivo fungicidal activity against Rhizoctonia solani . Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations showed that treatment with compound A21 induced significant morphological changes in R. solani mycelia, including the cell membrane contraction. Transcriptomic analysis indicated that differentially expressed genes (DEGs) in R. solani treated with compound A21 were significantly enriched in pathways related to the carbohydrate metabolism and lipid metabolism, and the relative expression of representative DEGs was further validated by quantitative real‐time polymerase chain reaction (qRT‐PCR). The increase in ergosterol content suggested that R. solani may counteract the drug stress of amidohydrazide compounds by enhancing ergosterol biosynthesis. Toxic assessment demonstrated that zebrafish exposed to compound A21 had survival rates of 90% at 1 μg mL −1 and 60% at 10 μg mL −1 within 72 h. Additionally, hydrolysis behavior in different pH buffers indicated that these compounds displayed rapid hydrolysis rates in the pH 9.18 buffer, while maintaining relatively high stability in the pH 4.01 and 6.86 buffers. CONCLUSION Amidohydrazide compounds have exhibited excellent fungicidal efficacy and hold great promise as a bioactive pharmacophore for the development of new environmentally friendly fungicides, thereby ensuring food supply and security. © 2025 Society of Chemical Industry.