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Synthesis and bioevaluation of pyrazole-benzimidazolone hybrids as novel human 4-Hydroxyphenylpyruvate dioxygenase inhibitors.

Abstract
4-Hydroxyphenylpyruvate dioxygenase (HPPD), an essential enzyme in tyrosine catabolism, is an important target for treating type I tyrosinemia. Inhibition of HPPD can effectively alleviate the symptoms of type I tyrosinemia. However, only one commercial HPPD inhibitor, 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione (NTBC), has been available for clinical use so far. In the present study, a series of novel pyrazole-benzimidazolone hybrids were designed, synthesized and evaluated as potent human HPPD inhibitors. Most of the new compounds displayed significant inhibitory activity against the recombinant human HPPD. Moreover, compound 9l was identified as the most potent candidate with IC50 value of 0.021 μM against recombinant human HPPD, about 3-fold more potent than NTBC. Thus the pyrazole-benzimidazolone hybrid has great potential to be further developed for the treatment of type I tyrosinemia.
AuthorsYu-Ling Xu, Hong-Yan Lin, Xu Ruan, Sheng-Gang Yang, Ge-Fei Hao, Wen-Chao Yang, Guang-Fu Yang
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 92 Pg. 427-38 (Mar 06 2015) ISSN: 1768-3254 [Electronic] France
PMID25590863 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Benzimidazoles
  • Enzyme Inhibitors
  • Pyrazoles
  • benzimidazolone
  • pyrazole
  • 4-Hydroxyphenylpyruvate Dioxygenase
Topics
  • 4-Hydroxyphenylpyruvate Dioxygenase (antagonists & inhibitors, metabolism)
  • Benzimidazoles (chemistry, pharmacology)
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyrazoles (chemistry, pharmacology)
  • Structure-Activity Relationship

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