(4-Hydroxyphenyl)pyruvate dioxygenase (HPPD) is a non-heme Fe(II) enzyme that catalyzes the conversion of (4-hydroxyphenyl)pyruvate (HPP) to homogentisate as part of the tyrosine catabolism pathway. Inhibition of HPPD by the triketone 2-[2-nitro-4-(trifluoromethyl)benzoyl]- 1,3- cyclohexanedione (NTBC) is used to treat type I tyrosinemia. In the present study, we elucidated the structure-based design of series of pyrazolone derivatives as novel potent human 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 inhibitor 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, π-π interaction and chelation. References: 1. Kyung Hee Kim, Maike Petersen. Plant Science 2002,163, 1001-1009 2. Kayunta Johnson-Winters, Vincent M. Purpero, Michael Kavana, Tamara Nelson, and Graham R. Moran*. Biochemistry 2003, 42, 2072-2080 3. Alphonso A. Amaya, Kotanee T. Brzezinski, Natasha Farrington, and Graham R. Moran*. Archives of Biochemistry and Biophysics 2004,421. 135–142.

Design and bioevaluation of novel human 4-hydroxyphenylpyruvate dioxygenase inhibitors

249th National Meeting (2015)

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