4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27), converting 4- hydroxyphenyl pyruvate acid (HPPA) to homogentisate (HGA), is very important for the biosynthesis of the plastoquinone and tocopherol which are essentially required for normal growth of plants. Inhibitors targeting HPPD were discovered as potent herbicides, due to the blockage of HPPA-HGA conversion and thereafter lead to the intense bleaching and even death of weeds. In the present study, we elucidated the structure-based design of series of pyrazolone derivatives as novel potent HPPD inhibitors. Among those new inhibitors, compound 2e  with Ki value of 0.88 nM was identified as the most promising herbicide candidate, significantly more potent than the commercially available HPPD inhibitors, including mesotrion, sulcotrione and NTBC. To our knowledge, this is the first HPPD inhibitor with a potency of subnanomolar Ki value discovered through structure-based design. The subsequent mechanism study based on molecular modeling and site-directed mutagenesis indicated that, 2e  strongly binds in HPPD through notable hydrophobic interaction, p-p interaction and chelation.

Discovery of novel 4-hydroxyphenylpyruvate dioxygenase inhibitors as potential herbicides

248th National Meeting (2014)

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