DISCOVERY OF TRIKETONE-QUINOXALINE HYBRIDS AS POTENT HPPD INHIBITORS USING STRUCTURE-BASED DRUG DESIGN

doi:10.15302/J-FASE-2021401

Front. Agr. Sci. Eng.

2022, Vol. 9

Issue (1) : 133-145 https://doi.org/10.15302/J-FASE-2021401

RESEARCH ARTICLE

DISCOVERY OF TRIKETONE-QUINOXALINE HYBRIDS AS POTENT HPPD INHIBITORS USING STRUCTURE-BASED DRUG DESIGN

Baifeng ZHENG, Yaochao YAN, Can FU, Guangyi HUANG, Long ZHAO, Qiong CHEN(

), Renyu QU(

), Guangfu YANG

Key Laboratory of Pesticides & Chemical Biology of the Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, China.

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Abstract

• HPPD is one of the most promising targets for new herbicides.

• A family of novel HPPD inhibitors based on the triketone-quinoxaline scaffold was designed and synthesized.

• One particular product (7d) gave the highest inhibition of HPPD of the newly synthesized derivatives.

• Triketone-quinoxaline derivatives provide a useful molecular scaffold for the discovery of novel HPPD-inhibiting herbicides.

p-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) belongs to the family of Fe(II)-dependent non-heme oxygenases that occur in the majority of aerobic organisms. HPPD has proved to be a promising target in herbicide research and development. A battery of novel triketone-quinoxaline compounds has been designed using a structure-based drug design strategy and then prepared. Enzyme inhibition assays show that these synthesized derivatives possess favorable inhibition capability against Arabidopsis thaliana HPPD with IC₅₀ values ranging from 0.317 to 0.891 μmol·L⁻¹. Subsequently, the molecular docking results indicate that two adjacent carbonyls of the triketone moiety of the representative compound 2-(2,3-dimethyl-8-(o-tolyl)quinoxaline-6-carbonyl)-3-hydroxycyclohex-2-en-1-one (7d) engage in chelation with the ferrous ion of A. thaliana HPPD in a bidentate pose, and its quinoxaline scaffold forms two sets of parallel π-stacking interaction between two phenylalanine residues (Phe424 and Phe381). In addition, the extended phenyl group also interacts with Phe392 in a π-π stacking way. This study indicates that triketone-quinoxaline is a promising scaffold for discovering HPPD inhibitors with substantially increased potency, providing insight into the molecular design of new herbicides.

Keywords herbicide HPPD inhibitor quinoxaline triketon

Corresponding Author(s): Qiong CHEN,Renyu QU

Just Accepted Date: 27 May 2021 Online First Date: 13 July 2021 Issue Date: 17 January 2022

Cite this article:

Baifeng ZHENG,Yaochao YAN,Can FU, et al. DISCOVERY OF TRIKETONE-QUINOXALINE HYBRIDS AS POTENT HPPD INHIBITORS USING STRUCTURE-BASED DRUG DESIGN[J]. Front. Agr. Sci. Eng. , 2022, 9(1): 133-145.

URL:

https://academic.hep.com.cn/fase/EN/10.15302/J-FASE-2021401
https://academic.hep.com.cn/fase/EN/Y2022/V9/I1/133

Fig.1 Molecular design strategy of new triketone-quinoxaline HPPD inhibitors 7a–7q based on the commercial mesotrione using SBDD. (A) Binding model of AtHPPD-mesotrione complex (PDB ID: 5YWG). (B) Docking model of the parent scaffold of the triketone-quinoxaline hybrids with AtHPPD.

Fig.2 The synthetic route of triketone-quinoxaline derivatives 7a–7q. Reagents and conditions: (A) NBS, DMF, –5°C; (B) Raney Ni/H₂, MeOH, room temperature; (C) NH₄Cl, MeOH, reflux; (D) K₃PO₄·3H₂O, Pd(OAc)₂, reflux; (E) DMG·HCl, CuI, Cs₂CO₃, dioxane, 126–130°C, microware; (F) CMPI, cyclohexane-1,3-dione, Et₃N, dichloromethane, room temperature; (G) Et₃N, acetone cyanohydrin, CH₃CN, 25–30°C; (H) 1 mol·L⁻¹ HCl.

Tab.1 Inhibitory activity of triketone-quinoxaline derivatives against AtHPPD

Tab.2 Binding free energy calculations of compound 7d and mesotrione (kJ·mol⁻¹)

Fig.3 (A) Binding mode of HPPD inhibitor 7d with AtHPPD. The chelation interactions are depicted as red dashed lines and compound 7d is shown as cyan. (B) Superposition of binding modes of compound 7d (cyan) and mesotrione (orange) in AtHPPD.

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