Discovery of Pyrazole-Benzimidazolin-2-One Derivatives as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

Abstract

4-Hydroxyphenylpyruvate dioxygenase (HPPD) has become an attractive target for herbicide development owing to the slow development and low risk of resistance to its inhibitors. However, most available HPPD inhibitors exhibit limited crop selectivity and poor efficacy against grasses. Therefore, the exploration of novel molecular scaffolds is of great research value. In this study, we adopted a ring-fusion strategy to enhance π–π stacking interactions and developed a structurally novel pyrazole-4-chloro-benzimidazolin-2-one scaffold. Through systematic structural optimization, compound II-19 showed the strongest enzyme inhibitory activity, with an IC50 of 52 nM, about 6-fold higher potency than the positive control, mesotrione. The crystal structure of AtHPPD-II-19 revealed that the inhibitor engages in characteristic chelation and π–π stacking interactions within the active site, and the 3-NO2-benzyl group contributes additional hydrophobic interactions and a possible weak water-mediated interaction involving Gln293. Additionally, I-5 showed excellent broad-spectrum weed control and good safety toward peanut at 30 g a.i./ha. These results indicate that compound I-5 is a promising candidate for the development of new HPPD inhibitors for weed control in peanut fields.