Novel Benzodiazaborine Derivatives as Potent Antifungal Agents Targeting Leucyl-tRNA Synthase: Synthesis, Bioactivity, and In Silico Study

The search for novel antifungal drugs is driven by the rise of drug-resistant fungal infections. This study aimed to develop benzodiazaborine derivatives targeting leucyl-tRNA synthase and evaluate their antifungal activity. A total of 35 derivatives were designed, synthesized, and tested against six common phytopathogenic fungi. The in vitro tests identified several potent compounds, especially compounds 1, 2, and 3, with compound 3 (EC50 = 0.3837 μg/mL) outperforming boscalid (EC50 = 1.3446 μg/mL) against Rhizoctonia solani. Compounds 2, 9, and 13 also showed promising in vivo activity. Scanning electron microscopy analysis revealed that compounds 9 and 13 significantly disrupted Valsa mali hyphal morphology. A three-dimensional quantitative structure-activity relationship model and molecular docking studies with Thermus thermophilus LeuRS enzymes provided insights into the antifungal mechanisms. In conclusion, the benzodiazaborine derivatives 1, 2, 3, 9, and 13 show excellent potential as agricultural antifungal agents for further development.