To address the growing resistance and environmental issues of existing fungicides, the development of novel broad-spectrum fungicides based on new targets, such as TPS1, has been prioritized. However, related research remains limited. In this study, we optimized our previously reported isopropanolamine-based MoTPS1 inhibitor, j11, by replacing its groups on both sides of its isopropanolamine linker with sulfonamide and 1,2,4-triazole fragments through a fragment replacement combining rational design approach. This approach led to the identification of novel isopropanolamine compounds, including g12, g18, o1, and o3, exhibiting significantly improved TPS1 inhibition compared to j11, with IC₅₀ values against MoTPS1 and BcTPS1 of 8.38–14.73 and 38.70-59.99 μM, respectively. The interaction mechanism research confirmed that hydrogen bonds and salt bridges between the novel isopropanolamine compounds and the Glu396 residue in MoTPS1 were crucial during their interaction. Plant leaf and fruit inoculation experiment revealed that these novel isopropanolamine compounds exhibiting substantial inhibition against MoTPS1 and BcTPS1 significantly suppressed the infection of Magnaporthe oryzae and Botrytis cinerea. Preliminary fungicidal mechanism studies indicated that these novel isopropanolamine compounds disrupted various fungal physiological processes including sporulation, conidia germination, appressorium formation, and turgor pressure accumulation within appressorium, while also causing conidia deformation. The hyphal growth inhibition assay against various plant pathogenic fungi suggested that the novel isopropanolamine compounds such as o1 and o3 held the potential as broad-spectrum fungicide candidates with EC₅₀ values of 2.80-17.55 μg/mL. The toxicological assessment suggested that compounds o1 and o3 had no potential toxicity towards diverse non-target organisms. This study provided a valuable insight for optimizing and developing high effective TPS1 inhibitors to be applied in the control of plant diseases.

中文翻译：

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基于异丙醇胺的高效 TPS1 抑制剂的结构优化和发现作为有前途的广谱杀菌剂候选剂


为了解决现有杀菌剂日益增长的耐药性和环境问题，基于新靶点（如 TPS1）的新型广谱杀菌剂的开发已被优先考虑。然而，相关研究仍然有限。在这项研究中，我们优化了我们之前报道的基于异丙醇胺的 MoTPS1 抑制剂 j11，通过片段替换结合理性设计方法的片段替换其异丙醇胺接头两侧的基团和 1,2,4-三唑片段。这种方法导致鉴定出新型异丙醇胺化合物，包括 g12、g18、o1 和 o3，与 j11 相比，TPS1 抑制作用显著改善，对 MoTPS1 和 BcTPS1 的 IC ₅₀ 值分别为 8.38-14.73 和 38.70-59.99 μM。相互作用机制研究证实，新型异丙醇胺化合物与 MoTPS1 中的 Glu396 残基之间的氢键和盐桥在它们的相互作用过程中至关重要。植物叶片和果实接种实验表明，这些新型异丙醇胺化合物对 MoTPS1 和 BcTPS1 表现出显著抑制作用，显著抑制了米瘟病菌和灰霉菌的侵染。初步杀真菌机制研究表明，这些新型异丙醇胺化合物破坏了各种真菌生理过程，包括孢子形成、分生孢子萌发、贴生层形成和贴生层内的膨胀压力积累，同时也导致分生孢子变形。针对各种植物病原真菌的菌丝生长抑制试验表明，新型异丙醇胺化合物如 o1 和 o3 具有作为广谱杀菌剂候选的潜力，EC ₅₀ 值为 2.80-17.55 μg/mL。 毒理学评估表明，化合物 o1 和 o3 对多种非目标生物没有潜在毒性。本研究为优化和开发用于植物病害防控的高效 TPS1 抑制剂提供了有价值的见解。