Pest management science · 2026
Design, synthesis, and quantitative structure-activity modeling of indole-3-pyrimidine hydrazone derivatives as novel antifungal agents.
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Zhang Hanbao, Wu Ye, Guo Tongyu, Xiao Lei, Chen Chunxia, Lei Yining, Fan Lihong, Zhao Xinyi, Shi Lianxu, Peng Jinsong
Аннотация
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: 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.
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.
RESULTS: 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.
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.