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Design, synthesis, and biological evaluation of N-(3-cyano-1H-indol-5/6-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamides and 5-(6-oxo-1,6-dihydropyrimidin-2-yl)-1H-indole-3-carbonitriles as novel xanthine oxidase inhibitors

化学 吲哚试验 立体化学 黄嘌呤氧化酶 别嘌呤醇 药效团 效力 部分 IC50型 酰胺 非布索坦 高尿酸血症 体外 生物化学 尿酸 病理 医学
作者
Bing Zhang,Yulin Duan,Yuwei Yang,Qing Mao,Fengwei Lin,Jun Gao,Xiwen Dai,Peng Zhang,Qiuhua Li,Jinxin Li,Ronghua Dai,Shaojie Wang
出处
期刊:European journal of medicinal chemistry [Elsevier BV]
卷期号:227: 113928-113928 被引量:24
标识
DOI:10.1016/j.ejmech.2021.113928
摘要

Xanthine oxidase (XO) has been an important target for the treatment of hyperuricemia and gout. The analysis of potential interactions of pyrimidinone and 3-cyano indole pharmacophores present in the corresponding reported XO inhibitors with parts of the XO active pocket indicated that they both can be used as effective fragments for the fragment-based design of nonpurine XO inhibitors. In this paper, we adopted the fragment-based drug design strategy to link the two fragments with an amide bond to design the type 1 compounds 13a-13w,14c, 14d, 14f, 14g, 14j, 14k, and 15g. Compound 13g displayed an evident XO inhibitory potency (IC50 = 0.16 μM), which was 52.3-fold higher than that of allopurinol (IC50 = 8.37 μM). For comparison, type 2 compounds 5-(6-oxo-1,6-dihydropyrimidin-2-yl)-1H-indole-3-carbonitriles (25c-25g) were also designed by linking the two fragments with a single bond directly. The results showed that compound 25c from the latter series displayed the best inhibitory potency (IC50 = 0.085 μM), and it was 98.5-fold stronger than that of allopurinol (IC50 = 8.37 μM). These results suggested that amide and single bonds were applicable for linking the two fragments together to obtain potent nonpurine XO inhibitors. The structure-activity relationship results revealed that hydrophobic groups at N-atom of the indole moiety were indispensable for the improvement of the inhibitory potency in vitro against XO. In addition, enzyme kinetics studies suggested that compounds 13g and 25c, as the most promising XO inhibitors for the two types of target compounds, acted as mixed-type inhibitors for XO. Moreover, molecular modeling studies suggested that the pyrimidinone and indole moieties of the target compounds could interact well with key amino acid residues in the active pocket of XO. Furthermore, in vivo hypouricemic effect demonstrated that compounds 13g and 25c could effectively reduce serum uric acid levels at an oral dose of 10 mg/kg. Therefore, compounds 13g and 25c could be potential and efficacious agents for the treatment of hyperuricemia and gout.
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