School of Pharmacy, Jinzhou Medical University, Jinzhou 121001, PR China.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China.
Bioorg Med Chem Lett. 2020 Apr 1;30(7):126969. doi: 10.1016/j.bmcl.2020.126969. Epub 2020 Jan 18.
In this work, according to the 'me-too me-better' design strategy, a peculiar side chain different from lefamulin at C14 position of pleuromutilin was introduced. A series of novel thioether pleuromutilin derivatives containing cyclohexane in the C14 chain was synthesized by ten-step synthesis reaction. All derivatives were characterized by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometer (HRMS). Furthermore, majority of derivatives displayed moderate antibacterial activity in vitro. However, the compound 2C and 2J exhibited comparable or superior antibacterial activity to lefamulin. The summarized structure-activity relationship not only made the variety of pleuromutilin derivatives more diverse, but also provided new ideas for its design and development.
在这项工作中，根据“me-too me-better”设计策略，在截短侧耳素 C14 位置引入了一个与 lefamulin 不同的特殊侧链。通过十步合成反应，合成了一系列新型含环己烷 C14 链的硫醚截短侧耳素衍生物。所有衍生物均通过核磁共振（NMR）和高分辨率质谱（HRMS）进行了表征。此外，大多数衍生物在体外均显示出中等的抗菌活性。然而，化合物 2C 和 2J 的抗菌活性与 lefamulin 相当或优于 lefamulin。总结的构效关系不仅使截短侧耳素衍生物的种类更加多样化，而且为其设计和开发提供了新的思路。
