Abstract
<List> <ListItem><ItemContent> • HPPD is one of the most promising targets for new herbicides. </ItemContent></ListItem> <ListItem><ItemContent> • A family of novel HPPD inhibitors based on the triketone-quinoxaline scaffold was designed and synthesized. </ItemContent></ListItem> <ListItem><ItemContent> • One particular product (7d) gave the highest inhibition of HPPD of the newly synthesized derivatives. </ItemContent></ListItem> <ListItem><ItemContent> • Triketone-quinoxaline derivatives provide a useful molecular scaffold for the discovery of novel HPPD-inhibiting herbicides. </ItemContent></ListItem></List> <i>p</i>-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 <i>Arabidopsis thaliana</i> HPPD with IC<sub>50</sub> values ranging from 0.317 to 0.891 μmol·L<sup>−</sup><sup>1</sup>. 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 <i>A. thaliana</i> 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.
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