title: 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.
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Xu
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Xu
authors.initials: X
authors.lastname: Ruan
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Sheng-Gang
authors.initials: SG
authors.lastname: Yang
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Ge-Fei
authors.initials: GF
authors.lastname: Hao
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China. Electronic address: tomyang@mail.ccnu.edu.cn.
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Yang
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China; Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 30071, PR China. Electronic address: gfyang@mail.ccnu.edu.cn.
authors.forename: Guang-Fu
authors.initials: GF
authors.lastname: Yang
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D011720:Pyrazoles; C014353:benzimidazolone; C031280:pyrazole; D015111:4-Hydroxyphenylpyruvate Dioxygenase
keywords: 4-Hydroxyphenylpyruvate dioxygenase; Benzimidazolone; Inhibitors; Type I tyrosinemia