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

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

Dingfeng Luo et al. J Adv Res. 2024 Aug.

Abstract

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 essentialenzyme 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-2-chlorophenoxy) acetyl)piperazin-1-yl)acetamido) terephthalate (Compound 9ay, EC50 = 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-phosphate-dependent enzymes.

Keywords: Crystal structure; Herbicide target; In silico screening; Serine hydroxymethyltransferase (SHMT); Synthesis.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

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Graphical abstract
Fig. 1
Fig. 1

The 3D X-ray crystal structure of CcSHMT1. A: The details of relevant refinement statistics; B and C: the overall structure (the obverse, B) and (the reverse, C) of CcSHMT1 at 2.8 Å resolution. D: the three domains of the CcSHMT1 monomer, the N-terminus, the large domain, and the C-terminus. F: the omit map for the PLP ligand in the overall structure. PLP: pyridoxal-5-phosphate. PLP binds with Ser146, Asp253, His281, and Lys282 through hydrogen bonds in the α-helices and binds with Gly327 through hydrogen bonds in the β-strand.

Fig. 2
Fig. 2

The virtual screening process and biological activity of compounds A1-A20. A: The virtual screen-based discovery process. B: Docking diagram of SHMT (light green) and compound A8 (carmine), Oxygen (red), nitrogen (blue), and hydrogen (white) are indicated. C: Inhibition ratio of compounds A1-A20 on CcSHMT1 in vitro at a dosage of 100 mg/L. D-E: Inhibitory effects of compounds A1-A20 on Amaranthus retroflexus (D) and Echinochloa crusgalli (E) at a dosage of 100 mg/L after 7 day. Data are presented as the SE of the mean (n = 3). F: Compounds A1-A11, A13-A14, and A16-A20 using pharmacophore models could be divided into N-phenylacetamide derivatives, substituted benzyl-thick heterocyclic derivatives, and furan-carboxylic acid/thiophene-carboxamides. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3
Fig. 3

Synthesis route to CcSHMT1 inhibitor derivatives 9aa-9bf. Reagents and conditions consisted of a: 2-bromoacetyl chloride and terephthalate (THF) at room temperature; b: N-Boc-piperazine, potassium carbonate and DMF at 60 °C; c: trifluoroacetic acid and dichloromethane at room temperature; d: methyl 2-bromoacetate, potassium carbonate and DMF at 60 °C; e: sodium hydroxide, methanol and hydrochloric acid; f: oxalyl chloride and dichloromethane; and g: triethylamine and dichloromethane.

Fig. 4
Fig. 4

Herbicidal activity and crop selectivity of CcSHMT1 inhibitor derivatives 9aa-9bf. Herbicidal bioassay of 9ao and 9ay with controls 2,4-D and CAP targeting Echinochloa crusgalli, Amaranthus retroflexus, Lactuca sativa, Lolium perenne, and Conyza canadensis at 100 mg/L A: pre-emergence and B: post-emergence; C: Inhibitor effect of Conyza canadensis with 9ao and 9ay treatment (0.43 mM-5.16 mM) after 7 day (Bar = 1 cm); D: The safety of maize under 9ao and 9ay with controls 2,4-D and CAP at 750 g a.i./ha after 7 day (Bar = 5 cm). E and F: Weed control efficacy of 9ay (180 and 360 g a.i./ha) with controls 2,4-D (375 g a.i./ha) and CAP (375 g a.i./ha) after 14 day in field trials (Bar = 5 cm). Data are presented as SE of the mean (n = 3).

Fig. 5
Fig. 5

The targeting ability of 9ay on CcSHMT1. A: The influence of ultrastructural characteristics of mitochondria in Conzya canadensis leaves 4 h after 9ay treatment (375 g a.i./ha, Bar = 500 nm) and the untreated control (Bar = 1 μm). ST: starch grain; CP: chloroplast; CW: cell wall; MC: mitochondria; VA: vacuole. Inhibition ratio of CcSHMT1 in vitro by B: 9ay (1, 1.5, 5, 10, 15, 20 mM) and C: CAP (0.63, 3.16, 6.32, 18.96, 31.6, 44.24, 63.2 μM). D: The phenotype of overexpressing lines and wild type under 9ay treatment (1, 300 g a.i./ha) after 7 day (Bar = 2 cm). E: Inhibition of overexpressing CcSHMT1 lines and the wild type by 9ay (750, 900, 1150, 1300, 1750 g a.i./ha) after 7 day. F: Inhibition of CcSHMT1 in vivo by 9ay (300 and 500 g a.i./ha); G: The influence of 9ay (300 and 500 g a.i./ha) on H2O2 content in CcSHMT1 overexpressing lines and the wild type.

Fig. 6
Fig. 6

Model of target structure-based discovery and synthesis of small molecule inhibitors with herbicidal activity toward CcSHMT1. We first resolved the CcSHMT1 structure. To select potential inhibitors of CcSHMT1 (PDB: 7E13), the compounds were interacted with key CAP binding pocket residues, which is Ser146, Pro169, Tyr178, and Lys410. Though virtual screening and biological assays of potential CcSHMT1 inhibitors, a pharmacophore compound was found that had excellent herbicidal activity. Novel CcSHMT1 inhibitor derivatives of the target compounds were designed and synthesized, and their herbicidal activity was determined in greenhouse and field trials. The “druggability” of compound 9ay, a first-in-class small molecule, inhibited CcSHMT1. Compound 9ay could be developed as a potential herbicide for weed management in monocotyledon crop fields.

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