Design, synthesis and biological activity of novel pyrazole-quinazoline-2,4-diones as 4-hydroxyphenylpyruvate dioxygenase inhibitors

In recent years, inhibitors targeting 4-hydroxyphenylpyruvate dioxygenase (HPPD) have become the hot research in the field of herbicide due to their high activity and low risk of resistance. Quinazoline-2,4-dione has been proved to be a potent scaffold. To further exploit its advantage, 30 novel pyrazole-quinazoline-2,4-dione derivatives were designed and synthesized based on the previous work and existing structure-activity relationship, all the structure of which were determined by HRMS, ¹H NMR and ¹³C NMR. Furthermore, the in vitro and in vivo activity of the synthesized compounds were evaluated. The result indicated that most of the synthesized compounds exhibited comparable or even better enzyme inhibitory activity than that of the positive control benquitrione. The greenhouse herbicidal activity experiments revealed that the tested compounds showed growth inhibition against the six tested weeds, especially for compound 9-28 , which achieved more than 80% inhibition against the six species of target weeds at the dosage of 150 g/hm² and 100% inhibition against Echinochloa crus-galli and Digitaria sanguinalis. Furthermore, the AtHPPD- 9-28 complex was obtained, which explained the binding mode between the inhibitor and target enzyme, and brought a novel thought to facilitate a detailed understanding for the discovery of new HPPD inhibitors with improved performance.