Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors.
Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors.
复制标题
DOI：
10.1016/j.ejmech.2016.10.024
复制
发表时间：
2016-11-29
影响因子：
6.7
通讯作者：
Fan E
中科院分区：
文献类型：
--
作者：
Huang W;Zhang Z;Barros-Álvarez X;Koh CY;Ranade RM;Gillespie JR;Creason SA;Shibata S;Verlinde CLMJ;Hol WGJ;Buckner FS;Fan E
采用结构指导的方法对布氏锥虫甲硫氨酰-tRNA合成酶的筛选命中1进行了优化。优化导致两个新的系列的有效抑制剂，环状接头和线性接头系列的鉴定。这两个系列的化合物在T.布鲁氏菌生长抑制试验，同时显示对哺乳动物细胞的低毒性。每个系列的最佳化合物16和31分别表现出39和22 nM的EC 50。化合物16和31在小鼠中口服给药后也表现出有希望的PK性质。此外，化合物31具有中等良好的脑渗透性，在IP注射后60分钟脑/血浆比为0.27。这项研究为人类非洲锥虫病（HAT）的新治疗提供了新的先导化合物。
A screening hit 1 against Trypanosoma brucei methionyl-tRNA synthetase was optimized using a structure-guided approach. The optimization led to the identification of two novel series of potent inhibitors, the cyclic linker and linear linker series. Compounds of both series were potent in a T. brucei growth inhibition assay while showing low toxicity to mammalian cells. The best compound of each series, 16 and 31, exhibited EC50s of 39 and 22 nM, respectively. Compounds 16 and 31 also exhibited promising PK properties after oral dosing in mice. Moreover, compound 31 had moderately good brain permeability, with a brain/plasma ratio of 0.27 at 60 min after IP injection. This study provides new lead compounds for arriving at new treatments of human African trypanosomiasis (HAT).