Discovery of Triketone-Quinazolinone Hybrids as Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is a promising target for new herbicide research. To develop new HPPD-inhibiting herbicides, we used a scaffold-hopping strategy by introducing a quinazolinone ring and combining it with the classic triketone pharmacophore, designing and synthesizing a series of novel HPPD inhibitors with a fused-ring architecture. The results showed that II -series of compounds exhibited excellent inhibitory activity against Arabidopsis thaliana ( At ) HPPD, with IC 50 values 0.5- to 2.5-fold lower than those of mesotrione. Moreover, we obtained the crystal structure of At HPPD– II-36 complex at a resolution of 1.8 Å. Importantly, II-36 exhibited high safety to wheat and outstanding herbicidal efficacy against Echinochloa crus-galli , Digitaria sanguinalis , and Bromus japonicus at a dosage of 30 g ai/ha. Our study provides a valuable example for designing novel HPPD inhibitors with enhanced herbicidal activity and improved crop selectivity.