Amide-based xanthine oxidase inhibitors bearing an N-(1-alkyl-3-cyano-1H-indol-5-yl) moiety: Design, synthesis and structure-activity relationship investigation
Amide-based xanthine oxidase inhibitors bearing an N-(1-alkyl-3-cyano-1H-indol-5-yl) moiety: Design, synthesis and structure-activity relationship investigation
复制标题
带有 N-(1-烷基-3-氰基-1H-吲哚-5-基) 基团的酰胺基黄嘌呤氧化酶抑制剂：设计、合成和构效关系研究
DOI：
10.1016/j.bioorg.2021.105417
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发表时间：
2021-10-18
影响因子：
5.1
通讯作者：
Meng, Fan-Hao
中科院分区：
文献类型：
--
作者：
Zhang, Ting-Jian;Tu, Shun;Meng, Fan-Hao
我们之前的工作鉴定了一种有前途的基于异烟酰胺的黄嘌呤氧化酶（XO）抑制剂，N-（3-氰基-4-（（2-氰基苄基）氧基）苯基）异烟酰胺（1），并得出结论，酰胺是探索XO抑制剂化学空间的有效连接体，其完全不同于非布司他和托吡司他的五元环框架。吲哚，一种内源性生物活性物质和一种流行的药物构建片段，参与了本工作的结构优化活动。通过引入功能基团，合成了N-（1-烷基-3-氰基-1H-吲哚-5-基），缩短了1的3 '-氰基与XO的Asn 768残基之间的距离，从而弥补了1的3'-氰基与XO的Asn 768残基之间的氢键作用。在此背景下，合理设计并合成了8种杂环芳香酰胺类化合物，以研究酰胺类XO抑制剂的构效关系。优化的化合物a6（IC 50 = 0.018 μ M）表现出比初始化合物1（IC 50 = 0.31 μ M）提高17.2倍的效力。其效力与托吡司他相当（IC 50 = 0.013 μ M）。分子对接和分子动力学研究证明了氰基与Asn 768残基之间存在稳定的氢键。此外，口服a6（11.8 mg/kg）可有效降低急性高尿酸血症大鼠模型的血清尿酸水平。肝微粒体稳定性实验表明，化合物a6在大鼠肝微粒体中具有良好的代谢稳定性。然而，α 6的体内效力远低于托吡司他，这可以通过平行人工膜渗透性测定（PAMPA）中发现的吸收差来解释。此外，6a对正常细胞系MCF 10A和16 HBE无细胞毒性。总之，这项工作最终鉴定出化合物6a作为进一步探索酰胺基XO抑制剂的优秀先导化合物。
Our previous work identified a promising isonicotinamide based xanthine oxidase (XO) inhibitor, N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (1), and concluded that amide is an effective linker in exploring the XO inhibitor chemical space that is completely different from the five-membered ring framework of febuxostat and topiroxostat. Indole, an endogenous bioactive substance and a popular drug construction fragment, was involved in the structural optimization campaign of the present effort. After the installation of some functional groups, N-(1-alkyl-3-cyano-1H-indol-5-yl) was generated and employed to mend the missing H-bond interaction between the 3'-cyano of 1 and Asn768 residue of XO by shortening their distance. In this context, eight kinds of heterocyclic aromatic amide chemotypes were rationally designed and synthesized to investigate the structure activity relationship (SAR) of amide-based XO inhibitors. The optimized compound a6 (IC50 = 0.018 mu M) exhibits 17.2-fold improved potency than the initial compound 1 (IC50 = 0.31 mu M). Its potency is comparable to that of topiroxostat (IC50 = 0.013 mu M). Molecular docking and molecular dynamics studies proved the existence of the stable H-bond between the cyano group and the Asn768 residue. Moreover, oral administration of a6 (11.8 mg/kg) could effectively reduce serum uric acid levels in an acute hyperuricemia rat model. Liver microsomal stability assay illustrated that compound a6 possesses well metabolic stability in rat liver microsomes. However, the in vivo potency of a6 was much lower than that of topiroxostat, which may be explained by the poor absorption found in the parallel artificial membrane permeability assay (PAMPA). In addition, 6a has non-cytotoxicity against normal cell lines MCF10A and 16HBE. Taken together, this work culminated in the identification of compound 6a as an excellent lead for further exploration of amide-based XO inhibitors.