The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
Bioorg Med Chem Lett. 2019 Sep 15;29(18):2686-2689. doi: 10.1016/j.bmcl.2019.07.024. Epub 2019 Jul 16.
gem-Disubstituted N-heterocycles are rarely found in drugs, despite their potential to improve the drug-like properties of small molecule pharmaceuticals. Linezolid, a morpholine heterocycle-containing oxazolidinone antibiotic, exhibits significant side effects associated with human mitochondrial protein synthesis inhibition. We synthesized a gem-disubstituted linezolid analogue that when compared to linezolid, maintains comparable (albeit slightly diminished) activity against bacteria, comparable in vitro physicochemical properties, and a decrease in undesired mitochondrial protein synthesis (MPS) inhibition. This research contributes to the structure-activity-relationship data surrounding oxazolidinone MPS inhibition, and may inspire investigations into the utility of gem-disubstituted N-heterocycles in medicinal chemistry.
尽管含杂环的 N-杂环化合物有改善小分子药物类药性的潜力，但在药物中却很少见。含吗啉杂环的恶唑烷酮类抗生素利奈唑胺，具有显著的与人类线粒体蛋白合成抑制相关的副作用。我们合成了一种偕二取代的利奈唑胺类似物，与利奈唑胺相比，它对细菌保持相当（尽管略有降低）的活性，体外理化性质相当，并且降低了不希望的线粒体蛋白合成（MPS）抑制。这项研究为恶唑烷酮类 MPS 抑制的构效关系数据做出了贡献，并可能激发对偕二取代 N-杂环在药物化学中的应用的研究。
