Design, synthesis, and quantitative structure–activity modeling of indole‐3‐pyrimidine hydrazone derivatives as novel antifungal agents

BACKGROUND: Fungicides remain the primary approach for preventing and controlling agricultural and forestry fungal diseases. However, the inevitable emergence of antifungal drug resistance in plant pathogenic fungi necessitates novel multi-target fungicides. RESULTS: ) = 6.98, 6.62, and 8.18 μg/mL, respectively), outperforming the positive control azoxystrobin. In vivo trials revealed that IPH-18 (20 and 50 μg/mL) effectively suppressed Sphaeropsis sapinea infection, demonstrating bioactivity comparable to the commercial fungicide carbendazim. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) confirmed that IPH-18 disrupts pathogenic fungi by damaging submicro- and ultra-structural components (cell wall and membrane). Quantitative structure-activity relationship (QSAR) modeling further revealed that introducing unsaturated substituents and electronegative atoms significantly enhanced antifungal potency. Molecular docking simulation results demonstrate that compound IPH-18 displays promising multi-target inhibitory activity. The calculated binding energies for glycogen synthase, enoyl-CoA hydratase, glutathione S-transferase, monopolar spindle kinase 1 (Mps-1), and laccase were -8.12, -8.56, -8.05, -7.80, and -7.92 kcal/mol, respectively. CONCLUSIONS: The QSAR analysis of 34 novel indole-3-pyrimidine hydrazones, combined with molecular docking simulations, established a crucial theoretical foundation for developing multi-target fungicides by enabling structural optimization and elucidating precise fungicidal mechanisms of action. © 2026 Society of Chemical Industry.