2. Academic Validation
  3. Structural optimization and discovery of high effective isopropanolamine-based TPS1 inhibitors as promising broad-spectrum fungicide candidates

Structural optimization and discovery of high effective isopropanolamine-based TPS1 inhibitors as promising broad-spectrum fungicide candidates

  • Eur J Med Chem. 2025 Jun 5:290:117553. doi: 10.1016/j.ejmech.2025.117553.
Zhiyang Jiang 1,  Na Wang 1,  Jinxiu Chen 1,  Huan Xu 1,  Wenya Zhu 1,  Dongmei Shi 1,  Chen Qian 2,  Jie Shi 1,  Xinyue Hu 1,  Zhijian Xu 3,  Dongli Wang 2,  Xinling Yang 1,  Junfeng Liu 4,  Hongxia Duan 5
Affiliations

Affiliations

  • 1 Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, Key Laboratory of National Forestry and Grassland Administration on Pest Chemical Control, China Agricultural University, Beijing, 100193, China.
  • 2 Department of Plant Pathology, College of Plant Protection, China Agricultural University, Beijing, 100193, China.
  • 3 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 Department of Plant Pathology, College of Plant Protection, China Agricultural University, Beijing, 100193, China. Electronic address: jliu@cau.edu.cn.
  • 5 Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, Key Laboratory of National Forestry and Grassland Administration on Pest Chemical Control, China Agricultural University, Beijing, 100193, China. Electronic address: hxduan@cau.edu.cn.
PMID: 40153931 DOI: 10.1016/j.ejmech.2025.117553
Abstract

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.

Keywords

Fungicide candidates; Inhibitors; Isopropanolamine compounds; Structural optimization; Trehalose-6-phosphate synthase.

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