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, PR China.
Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing, 101149, PR China.
Eur J Med Chem. 2022 Mar 5;231:114145. doi: 10.1016/j.ejmech.2022.114145. Epub 2022 Jan 22.
A series of thiophene-benzenesulfonamide derivatives was designed and synthesized by exploring the structure-activity relationship of lead compounds 2,3-disubstituted thiophenes 25a and 297F as antituberculosis agents, which displayed potent antimycobacterial activity against drug-susceptible and clinically isolated drug-resistant tuberculosis. In particular, compound 17b, which had improved activity (minimum inhibitory concentration of 0.023 μg/mL) compared with the lead compounds, displayed good intracellular antimycobacterial activity in macrophages with a reduction of 1.29 log CFU. A druggability evaluation indicated that compound 17b had favorable hepatocyte stability, low cytotoxicity, and low hERG channel inhibition. Moreover, compound 17b exhibited modest in vivo efficacy in an acute mouse model of tuberculosis. In addition, the molecular docking study elucidated the binding mode of compound 17b in the active site of DprE1. Therefore, compound 17b may be a promising antituberculosis lead for further research.
设计并合成了一系列噻吩-苯磺酰胺衍生物，通过探索先导化合物 2,3-二取代噻吩 25a 和 297F 的结构-活性关系，这些化合物对耐多药和临床分离的耐药结核分枝杆菌具有很强的抗分枝杆菌活性。特别是化合物 17b 与先导化合物相比，活性得到了提高（最小抑菌浓度为 0.023μg/mL），在巨噬细胞中具有良好的抗分枝杆菌活性，CFU 减少了 1.29 个对数。药物评价表明，化合物 17b 具有良好的肝细胞稳定性、低细胞毒性和低 hERG 通道抑制作用。此外，化合物 17b 在结核急性小鼠模型中表现出适度的体内疗效。此外，分子对接研究阐明了化合物 17b 在 DprE1 活性位点的结合模式。因此，化合物 17b 可能是一种有前途的抗结核先导化合物，值得进一步研究。
