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 herbicid...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 mmol$L–1.Subsequently,the molecular docking results indicate that two adjacent carbonyls of the triketone moiety of the representative compound 2-(2,3-dimethyl-8-(o-tolyl)quinoxaline-6-carbonyl)-3-hydroxycyclohex-2-en-1-one(7d)engage in chelation with the ferrous ion of A.thaliana HPPD in a bidentate pose,and its quinoxaline scaffold forms two sets of parallelπ-stacking interaction between two phenylalanine residues(Phe424 and Phe381).In addition,the extended phenyl group also interacts with Phe392 in aπ-πstacking way.This study indicates that triketone-quinoxaline is a promising scaffold for discovering HPPD inhibitors with substantially increased potency,providing insight into the molecular design of new herbicides.展开更多
基金This work was supported by the National Key R&D Program of China(2018YFD0200100)the National Natural Science Foundation of China(31901910,21772058,and 21837001)the China Postdoctoral Science Foundation(2018M642880).
文摘p-Hydroxyphenylpyruvate dioxygenase(EC 1.13.11.27,HPPD)belongs to the family of Fe(II)-dependent non-heme oxygenases that occur in the majority of aerobic organisms.HPPD has proved to be a promising target in herbicide research and development.A battery of novel triketone-quinoxaline compounds has been designed using a structure-based drug design strategy and then prepared.Enzyme inhibition assays show that these synthesized derivatives possess favorable inhibition capability against Arabidopsis thaliana HPPD with IC50 values ranging from 0.317 to 0.891 mmol$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 parallelπ-stacking interaction between two phenylalanine residues(Phe424 and Phe381).In addition,the extended phenyl group also interacts with Phe392 in aπ-πstacking 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.
