抗细菌
化学
赫尔格
IC50型
药理学
体外
噻吩
结核分枝杆菌
细胞毒性
组合化学
立体化学
铅化合物
对接(动物)
生物化学
肺结核
生物物理学
有机化学
护理部
病理
生物
钾通道
医学
作者
Pengxu Wang,Sarah M. Batt,Bin Wang,Lei Fu,Rongfei Qin,Yu Lu,Gang Li,Gurdyal S. Besra,Haihong Huang
标识
DOI:10.1021/acs.jmedchem.1c00263
摘要
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 23j, 24f, 25a, and 25b exhibited potent in vitro 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 (IC50) = 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 25a with acceptable pharmacokinetic property demonstrated significant bactericidal activity in an acute mouse model of tuberculosis. Moreover, the molecular docking study of template compound 23j provides new insight into the discovery of novel antitubercular agents targeting DprE1.
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