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

doi:10.15302/J-FASE-2021401

Frontiers of Agricultural Science and Engineering

2022, Vol. 9

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

本期目录

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.

Key words： herbicide HPPD inhibitor quinoxaline triketon

收稿日期: 2021-01-31 出版日期: 2022-01-17

Corresponding Author(s): Qiong CHEN,Renyu QU

引用本文:

. [J]. Frontiers of Agricultural Science and Engineering, 2022, 9(1): 133-145.
Baifeng ZHENG, Yaochao YAN, Can FU, Guangyi HUANG, Long ZHAO, Qiong CHEN, Renyu QU, Guangfu YANG. DISCOVERY OF TRIKETONE-QUINOXALINE HYBRIDS AS POTENT HPPD INHIBITORS USING STRUCTURE-BASED DRUG DESIGN. Front. Agr. Sci. Eng. , 2022, 9(1): 133-145.

链接本文:

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

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