Novel Pyrazole-Quinoxaline Conjugates as Potent HPPD-Inhibiting Herbicides with Notable Crop Safety

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a vital target for Herbicide development. A series of pyrazole-quinoxaline conjugates were designed and synthesized via scaffold hopping and structural optimization. Bioassays revealed that B9 exhibited potent inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD) with an IC₅₀ of 0.11 μM, outperforming mesotrione (0.22 μM) and topramezone (0.48 μM). B18 achieved 100% control over six weeds at 75 g a.i./ha and retained full efficacy against three broadleaf weeds even at 18.75 g a.i./ha. Furthermore, B18 produced less than 20% injury to rice, wheat, cotton, and peanut at 150 g a.i./ha, exhibiting superior crop safety to topramezone (47%-72%). Molecular docking elucidated the binding mechanism of B18 with AtHPPD via Fe²⁺ coordination, π-π interactions, and hydrogen bonds. Fluorescence titration and microscale thermophoresis assays further confirmed strong binding of B9 and B18 to AtHPPD. This study demonstrated that B18 is a promising, safe, and efficient HPPD-inhibiting Herbicide candidate.