N-(3-cyano-1H-indol-5-yl)isonicotinamide and N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamide derivatives: Novel amide-based xanthine oxidase inhibitors
N-(3-cyano-1H-indol-5-yl)isonicotinamide and N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamide derivatives: Novel amide-based xanthine oxidase inhibitors
复制标题
N-(3-氰基-1H-吲哚-5-基)异烟酰胺和N-(3-氰基-1H-吲哚-5-基)-1H-苯并[d]咪唑-5-甲酰胺衍生物：新型酰胺基
DOI：
10.1016/j.bioorg.2021.105181
复制
发表时间：
2021-07-28
影响因子：
5.1
通讯作者：
Meng, Fan-Hao
中科院分区：
文献类型：
--
作者：
Tu, Shun;Zhang, Ting-Jian;Meng, Fan-Hao
我们以前的工作表明，酰胺是探索黄嘌呤氧化酶(XO)抑制剂化学空间的有效连接物，而这些XO抑制剂与非布索坦和托吡司坦完全不同。本工作以3-氰基-1H-吲哚-5-基为关键基团，设计合成了N-(3-氰基-1H-吲哚-5-基)异烟酰胺(2a-w)和N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamides(3a-i)两个系列的酰胺类XO抑制剂。构效关系研究表明，N-(3-cyano-1-cyclopentyl-1H-indol-5-yl)-1H-benzo[d]咪唑-5-甲酰胺(3I，IC_(50)=0.62mU·M)是最有前景的化合物，体外抑制活性是别嘌醇(IC_(50)=8.91mU·M)的14.4倍。分子模拟为具有代表性的化合物提供了合理的相互作用模式。体内活性评价表明，化合物3I(12.8 mg/kg)对高尿酸钾诱导的高尿酸血症大鼠有明显的降尿作用。细胞毒性试验和ADME预测也支持3I是进一步探索酰胺类XO抑制剂的良好先导。
Our previous work demonstrated that amide is an efficient linker to explore chemical space of xanthine oxidase (XO) inhibitors that are entirely different from febuxostat and topiroxostat. In this effort, with 3-cyano-1H-indol-5-yl as a key moiety, two series of amide-based XO inhibitors, N-(3-cyano-1H-indol-5-yl)isonicotinamides (2a-w) and N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamides (3a-i), were designed and synthesized. The structure-activity relationship investigation identified N-(3-cyano-1-cyclopentyl-1H-indol-5-yl)-1H-benzo[d] imidazole-5-carboxamide (3i, IC50 = 0.62 mu M) as the most promising compound, with 14.4-fold higher in vitro inhibitory potency than allopurinol (IC50 = 8.91 mu M). Molecular simulations provided reasonable interaction modes for the representative compounds. Furthermore, in vivo activity evaluation demonstrated that compound 3i (oral dose of 12.8 mg/kg) has obviously hypouricemic effect on a potassium oxonate induced hyperuricemic rat model. Cytotoxicity assay and ADME prediction also supported that 3i is an excellent lead for further exploration of amide-based XO inhibitors.