Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China.
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, United States.
Bioorg Med Chem Lett. 2022 Jul 15;68:128761. doi: 10.1016/j.bmcl.2022.128761. Epub 2022 Apr 26.
Resistance to telithromycin and off-target effects associated with the metabolic instability present serious and challenging problems for the development of novel macrolides. Herein, studies of hybrids of macrolides and quinolones (termed macrolones) bridged with linkers from 11,12-cyclic carbamate of macrolides revealed different structure-activity relationships from the previously reported macrolones bridged with linkers derived from 6-, 9- and 4''-positions of macrolides. The optimized macrolone 34 g with a longer and rigid sidechain than telithromycin had improved metabolic stability compared to telithromycin (t: 110 vs 32 min), whose future has been heavily clouded by metabolic issues. Moreover, 34 g was 38-fold more potent than telithromycin against A2058/2059-mutated Mycoplasma pneumoniae (8 vs 315 μM), which may be attributed to a novel mode of action between the carboxylic acid of quinolone moiety and the bacterial ribosome. This work increases the prospect for discovery of novel and safe antibacterial agents to combat serious human infectious diseases.
耐替米星和与代谢不稳定性相关的非靶标效应是新型大环内酯类药物开发所面临的严重挑战。在此，通过将大环内酯类化合物的 11,12-环碳酸酯与连接子桥连，对大环内酯类化合物和喹诺酮类化合物（称为大环内酯类化合物）的杂种进行了研究，揭示了与先前报道的通过大环内酯类化合物的 6-、9-和 4''-位衍生的连接子桥连的大环内酯类化合物的不同结构-活性关系。与替米星相比，优化后的大环内酯类化合物 34g 具有比替米星更长更刚性的侧链，其代谢稳定性得到了改善（t：110 对 32min），替米星的未来因代谢问题而受到严重影响。此外，34g 对 A2058/2059 突变的肺炎支原体的活性比替米星高 38 倍（8 对 315μM），这可能归因于喹诺酮部分的羧酸与细菌核糖体之间的新作用模式。这项工作增加了发现新型安全抗菌剂以对抗严重人类传染病的前景。
