Benquitrione: A new HPPD-inhibiting herbicide with novel chemical scaffold

4-Hydroxyphenylpyruvate dioxygenase (HPPD) has been recognized as a promising target in both drug and pesticide discovery. With the aim to carry out structure-and-mechanism-based discovery of new HPPD inhibitors, we firstly determined the first crystal structure of Arabidopsis thaliana HPPD (AtHPPD) in complex with its natural substrate (HPPA). Structural comparison with holo-AtHPPD revealed that residue Gln293 underwent a remarkable rotation upon the HPPA binding by the formation of H-bond network of four residues (Ser267-Asn282-Gln307-Gln293), resulting the transformation of HPPD from an inactive state to active state. Based on the understanding of the substrate binding and catalytic mechanism, we proposed an inhibitor design strategy of blocking the transformation of HPPD from inactive state to active state. Therefore, a computational protocol was proposed and resulted in the successful discovery of the first commercial herbicide benquitrione with quinazoline-2,4-dione scaffold. Benquitrione exhibits excellent herbicidal activity against most of broadleaf weeds and some important grasses at the application dosage of 100~150 g.ai/ha, and excellent crop safety against sorghum, wheat, cotton, and maize. In addition, benquitrione shows excellent toxicological properties, its LD₅₀ for male and female rats were both over 5000 mg/kg. Moreover, no critical eye and skin irritation or skin sensitization was recognized on both active ingredient and formulation. No evidence of carcinogenicity, teratogenicity, and reproduction toxicity were observed in prolonged exposure studies. The toxicity toward nontarget aqueous species (fish, crustaceans, and algae), honeybees and birds were also quite low. Due to its excellent herbicidal activity, crop safety and toxicological properties, benquitrione has been approved in China and Pakistan as a new herbicide for the weed control in sorghum field, extended registrations to cotton and wheat are under way.