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A first-in-class dimethyl 2-acetamido terephthalate inhibitor targeting Conyza canadensis SHMT1 with a novel herbicidal mode-of-action

文献类型： 外文期刊

作者： Luo, Dingfeng 1 ; Bai, Zhendong 1 ; Bai, Haodong 1 ; Liu, Na 1 ; Han, Jincai 1 ; Ma, Changsheng 1 ; Wu, Di 1 ; Bai, Lianyang 1 ; Li, Zuren 1 ;

作者机构： 1.Hunan Acad Agr Sci, Hunan Prov Key Lab Biol & Control Weeds, Changsha 410125, Peoples R China

2.Hunan Univ, Coll Biol, Longping Branch, Changsha 410125, Peoples R China

关键词： Herbicide target; Serine hydroxymethyltransferase (SHMT); Crystal structure; In silico screening; Synthesis

期刊名称：JOURNAL OF ADVANCED RESEARCH （ 影响因子：11.4； 五年影响因子：11.0 ）

ISSN： 2090-1232

年卷期： 2024 年 62 卷

页码：

收录情况： SCI

摘要： Introduction: Herbicide application is a highly efficiency method of weed control that boots agricultural output and assures food security. The development of novel herbicides focuses on improved bioactivity and new modes of action. The amino acid biosynthesis was validated as a promising novel mode of action for herbicidal compounds. However, the amino acid biosynthesis enzyme remains largely unexplored for herbicidal targets. Objectives: Serine hydroxymethyl transferase (SHMT) is an essential enzyme in the photorespiratory cycle. The study aims to explore Conyza canadensis SHMT1 (CcSHMT1) as a promising target for herbicide discovery. Methods: Structure determination of CcSHMT1 was resolved by X-ray crystallography. Virtual screening docking experiments were performed with Glide version 5.5. Novel derivatives of dimethyl 2-acetamido terephthalate were further designed, synthesized, and bioassay. The druggability of the inhibitor was evidenced by ultrastructural changes in mitochondria, in vivo and vitro enzyme activity assays, and genetics analysis. Results: CcSHMT1 has a typical PLP-dependent enzyme 3D structure. The dimethyl 2-acetamido terephthalate-containing compounds had herbicidal activity. Dimethyl 2-(2-(4-(2-(4-bromo-2chlorophenoxy) acetyl)piperazin-1-yl)acetamido) terephthalate (Compound 9ay, , EC50 50 = 193.8 g a.i./ ha) exhibited the highest herbicidal activity on tested weed among the synthesized compounds. Compound 9ay had no obvious adverse effect on the growth of maize and honeybees. Compound 9ay was verified to target CcSHMT1 as an herbicide candidate. Conclusion: A first-in-class CcSHMT1 inhibitor that could be developed as a potent herbicide with a new mode of action and provide an avenue for discovering novel inhibitors of pyridoxal-5-phosphatedependent enzymes. (c) 2023 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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