Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation & Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China.
School of Biosciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
J Med Chem. 2021 May 13;64(9):6241-6261. doi: 10.1021/acs.jmedchem.1c00263. Epub 2021 Apr 14.
In this study, we report the design and synthesis of a series of novel thiophene-arylamide compounds derived from the noncovalent decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) inhibitor TCA1 through a structure-based scaffold hopping strategy. Systematic optimization of the two side chains flanking the thiophene core led to new lead compounds bearing a thiophene-arylamide scaffold with potent antimycobacterial activity and low cytotoxicity. Compounds , , , and exhibited potent activity against both drug-susceptible (minimum inhibitory concentration (MIC) = 0.02-0.12 μg/mL) and drug-resistant (MIC = 0.031-0.24 μg/mL) tuberculosis strains while retaining potent DprE1 inhibition (half maximal inhibitory concentration (IC) = 0.2-0.9 μg/mL) and good intracellular antimycobacterial activity. In addition, these compounds showed good hepatocyte stability and low inhibition of the human ether-à-go-go related gene (hERG) channel. The representative compound with acceptable pharmacokinetic property demonstrated significant bactericidal activity in an acute mouse model of tuberculosis. Moreover, the molecular docking study of template compound provides new insight into the discovery of novel antitubercular agents targeting DprE1.
在这项研究中，我们报告了一系列新型噻吩-芳酰胺化合物的设计和合成，这些化合物源自非共价的二磷酸核酮糖异构酶 1（DprE1）抑制剂 TCA1，采用了基于结构的支架跳跃策略。噻吩核心两侧链的系统优化导致了具有潜在抗分枝杆菌活性和低细胞毒性的新型噻吩-芳酰胺骨架的先导化合物。化合物 、 、 、 和 对敏感型（最低抑菌浓度（MIC）=0.02-0.12μg/mL）和耐药型（MIC=0.031-0.24μg/mL）结核菌株均具有很强的活性，同时保留了很强的 DprE1 抑制作用（半数最大抑制浓度（IC）=0.2-0.9μg/mL）和良好的细胞内抗分枝杆菌活性。此外，这些化合物具有良好的肝细胞稳定性和对人 ether-à-go-go 相关基因（hERG）通道的低抑制作用。具有可接受药代动力学特性的代表性化合物 在结核急性小鼠模型中表现出显著的杀菌活性。此外，模板化合物 的分子对接研究为发现针对 DprE1 的新型抗结核药物提供了新的见解。
