Design, synthesis, and quantitative structure-activity modeling of indole-3-pyrimidine hydrazone derivatives as novel...

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.

A series of novel indole-3-pyrimidine hydrazones were designed and synthesized using pharmacophore fusion/fragment hybridization strategies, with ferimzone, PMDD-5Y, melatonin, and chloroinconazide as lead compounds. All synthesized compounds exhibited inhibitory effects against the tested seven agricultural and forestry pathogens. Notably, compound IPH-18 exhibits excellent broad-spectrum activity, with inhibition rates exceeding 90% against Cytospora chrysosperma, Magnaporthe oryzae, and Fusarium graminearum at 50 μg/mL (half-maximal effective concentration (EC₅₀) = 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.

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.