Synthesis and bioevaluation of pyrazole-benzimidazolone hybrids as novel human 4-Hydroxyphenylpyruvate dioxygenase inhibitors
Synthesis and bioevaluation of pyrazole-benzimidazolone hybrids as novel human 4-Hydroxyphenylpyruvate dioxygenase inhibitors
复制标题
作为新型人类 4-羟基苯基丙酮酸双加氧酶抑制剂的吡唑-苯并咪唑酮杂化物的合成和生物评价
DOI：
10.1016/j.ejmech.2015.01.018
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发表时间：
2015-03-06
影响因子：
6.7
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
--
作者：
Xu, Yu-Ling;Lin, Hong-Yan;Yang, Guang-Fu
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 91 was identified as the most potent candidate with IC50 value of 0.021 mu M 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. (C) 2015 Elsevier Masson SAS. All rights reserved.
