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

•A series of pyrazole-benzimidazolone hybrids were designed by scaffold hopping strategy.•Most of the new compounds showed good activity against recombinant human HPPD.•Compound 9l was identified as the most potent candidate (IC50 = 21 nM), about 3-fold higher than NTBC.

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.

Graphical abstractA series of pyrazole-benzimidazolone hybrids were designed and synthesized as potent 4-hydroxyphenylpyruvate dioxygenase inhibitors. Compound 9l (IC50 = 21 nM) was the most potent candidate.Figure optionsDownload full-size imageDownload as PowerPoint slide