Structural optimization and discovery of high effective isopropanolamine-based TPS1 inhibitors as promising broad-spectrum fungicide candidates
文献类型：期刊论文
| 作者 | Jiang, Zhiyang2; Wang, Na2; Chen, Jinxiu2; Xu, Huan2; Zhu, Wenya2; Shi, Dongmei2; Qian, Chen1; Shi, Jie2; Hu, Xinyue2; Xu, Zhijian3
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2025-06-05 |
| 卷号 | 290页码:17 |
| 关键词 | Trehalose-6-phosphate synthase Structural optimization Isopropanolamine compounds Inhibitors Fungicide candidates |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2025.117553 |
| 英文摘要 | 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 mu M, 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 mu g/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. |
| WOS关键词 | PLANT INFECTION ; TREHALOSE ; METABOLISM ; RESISTANCE ; VIRULENCE ; PATHWAY |
| 资助项目 | National Key R & D Pro-gram of China[2022YFD1700200] ; National Key R & D Pro-gram of China[2023YFD1700700] ; National Natural Science Foundation of China[32172445] ; National Natural Science Foundation of China[31972289] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001459462100001 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316920]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Liu, Junfeng; Duan, Hongxia |
| 作者单位 | 1.China Agr Univ, Coll Plant Protect, Dept Plant Pathol, Beijing 100193, Peoples R China 2.China Agr Univ, Innovat Ctr Pesticide Res, Key Lab Natl Forestry & Grassland Adm Pest Chem Co, Coll Sci,Dept Appl Chem, Beijing 100193, Peoples R China 3.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Jiang, Zhiyang,Wang, Na,Chen, Jinxiu,et al. Structural optimization and discovery of high effective isopropanolamine-based TPS1 inhibitors as promising broad-spectrum fungicide candidates[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,290:17. |
| APA | Jiang, Zhiyang.,Wang, Na.,Chen, Jinxiu.,Xu, Huan.,Zhu, Wenya.,...&Duan, Hongxia.(2025).Structural optimization and discovery of high effective isopropanolamine-based TPS1 inhibitors as promising broad-spectrum fungicide candidates.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,290,17. |
| MLA | Jiang, Zhiyang,et al."Structural optimization and discovery of high effective isopropanolamine-based TPS1 inhibitors as promising broad-spectrum fungicide candidates".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 290(2025):17. |
入库方式： OAI收割
来源：上海药物研究所
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