2. Academic Validation
  3. Discovery of novel isopropanolamine inhibitors against MoTPS1 as potential fungicides with unique mechanisms

Discovery of novel isopropanolamine inhibitors against MoTPS1 as potential fungicides with unique mechanisms

  • Eur J Med Chem. 2023 Nov 15;260:115755. doi: 10.1016/j.ejmech.2023.115755.
Zhiyang Jiang 1,  Dongmei Shi 1,  Yitong Chen 2,  Huilin Li 1,  Jin'e Wang 1,  Xinrui Lv 1,  Yunjiang Zi 1,  Dongli Wang 2,  Zhijian Xu 3,  Jiaxing Huang 1,  Junfeng Liu 4,  Hongxia Duan 5
Affiliations

Affiliations

  • 1 Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, 100193, China; 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 CAS Key Laboratory of Receptor 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, China Agricultural University, Beijing, 100193, China; 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: 37672934 DOI: 10.1016/j.ejmech.2023.115755
Abstract

The resistance and ecotoxicity of fungicides seriously restrict our ability to effectively control Magnaporthe oryzae. Discovering fungicidal agents based on novel targets, including MoTPS1, could efficiently address this situation. Here, we identified a hit VS-10 containing an isopropanolamine fragment as a novel MoTPS1 inhibitor through virtual screening, and forty-four analogs were synthesized by optimizing the structure of VS-10. Utilizing our newly established ion-pair chromatography (IPC) and leaf inoculation methods, we found that compared to VS-10, its analog j11 exhibited substantially greater inhibitory activity against both MoTPS1 and the pathogenicity of M. oryzae. Molecular simulations clarified that the electrostatic interactions between the bridging moiety of isopropanolamine and residue Glu396 of contributed significantly to the binding of j11 and MoTPS1. We preliminarily revealed the unique fungicidal mechanism of j11, which mainly impeded the Infection of M. oryzae by decreasing sporulation, killing a small portion of conidia and interfering with the accumulation of turgor pressure in appressoria. Thus, in this study, a novel fungicide candidate with a unique mechanism targeting MoTPS1 was screened and discovered.

Keywords

Fungicidal mechanism; Inhibitor; Isopropanolamine compounds; Rice blast; Trehalose-6-phosphate synthase.

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