Discovery of Novel Thiophene-arylamide Derivatives as DprE1 Inhibitors with Potent Antimycobacterial Activities

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.

本研究报道了一系列新型噻吩芳酰胺类化合物的设计与合成：该类化合物以非共价结合的癸烯基磷酸-β-D-核糖2'-差向异构酶（decaprenylphosphoryl-β-d-ribose 2′-epimerase, DprE1）抑制剂TCA1为母核，通过基于结构的骨架跃迁策略获得。对噻吩母核两侧的侧链进行系统性优化后，研究人员得到了携带噻吩芳酰胺骨架的新型先导化合物，此类化合物兼具强效抗分枝杆菌活性与低细胞毒性。化合物23j、24f、25a及25b对药物敏感性（最低抑菌浓度（minimum inhibitory concentration, MIC）=0.02~0.12 μg/mL）与耐药性（MIC=0.031~0.24 μg/mL）结核分枝杆菌菌株均展现出优异的体外抗结核活性，同时保留了强效的DprE1抑制活性（半数抑制浓度（half maximal inhibitory concentration, IC50）=0.2~0.9 μg/mL）与良好的细胞内抗分枝杆菌活性。此外，此类化合物表现出良好的肝细胞稳定性，且对人类ether-à-go-go相关基因（human ether-à-go-go related gene, hERG）通道的抑制作用较弱。代表性化合物25a具备可接受的药代动力学特性，在急性结核小鼠感染模型中展现出显著的杀菌活性。此外，对模板化合物23j的分子对接研究，为靶向DprE1的新型抗结核药物研发提供了新的思路。