4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, 4-HPPD) belongs to the non-heme Fe(II)-containing enzymes family, which catalyzes the conversation of 4-hydroxyphenyl pyruvic acid (HPPA) into homogentisic acid (HGA), has known to be the mode of action of herbicides since the 1980s. It is an important enzyme in regulating the biosynthesis of tocopherols and plastoquinone. 4-HPPD-inhibiting herbicides can block photosynthesis, which will result in unique bleaching symptoms in sunlight and finally cause necrosis and death of treated plants. To discover of novel 4-HPPD inhibitors with high herbicidal activity and improved crop selectivity, a series of novel quinazoline-2,4-dione derivatives were designed and synthesized according to the structure of HPPD-inhibitor complex. Determination of the Ki values against A. thaliana4-HPPD indicated that most of the synthesized compounds displayed potent enzyme inhibition activity, some of which showed much higher potency than mesotrione. Further greenhouse assays indicated that most of the synthesized compounds displayed promising and broad-spectrum herbicidal activities at the dosages of 37.5-150 g ai/ha. Several crops, such as maize, rape, cotton and wheat exhibited high tolerance to some of these compounds at a concentration of 150 g ai/ha. These data indicated the great potential of further development of these compounds. In addition, the simulated binding modes showed that the exocyclic enol of compound I has a bidentate interaction with the ferrous form of the enzyme, the quinazoline-2,4-dione ring of compound I formed a sandwich p-p stacking interaction with Phe336 and Phe364.

Design and synthesis of novel quinazoline-2,4-dione derivatives as potent 4-HPPD inhibitors

248th National Meeting (2014)

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