Discovery of novel fluorine modification of aryloxyacetic acid derivatives as 4-hydroxyphenylpyruvate dioxygenase inhibitors

Abstract

Background

4-Hydroxyphenylpyruvate dioxygenase (HPPD) plays a crucial role in addressing issues related to plant protection research. To further our efforts in discovering new HPPD inhibitors, we adopted a bioisomerization strategy and designed a series of novel fluorinated aryloxyacetic acid scaffolds, building upon previously identified aryloxyacetic acid scaffolds. This study offers new insights into the discovery of innovative HPPD inhibitors. A series of novel HPPD inhibitor candidates (fluorinated derivatives of aryloxyacetic acids) were synthesized, and their activity was systematically evaluated using in vitro enzymatic methods and greenhouse experiments. Preliminary in vitro studies confirmed that these compounds effectively inhibit AtHPPD enzyme activity. Subsequent greenhouse experiments demonstrated that compounds 2,2-difluoro-1-(5‑hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-2-(4-phenoxyphenoxy) ethan-1-one and 2,2-difluoro-1-(5‑hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-2-(naphthalen-2-yloxy) ethan-1-one exhibited exceptional herbicidal activity against the tested weeds, outperforming Mesotrione under identical testing conditions. These findings suggest that fluorine-modified aryloxyacetic acid derivatives have the potential to serve as lead compounds in the development of HPPD inhibitors.