Department of Chemistry and Comparative Medicine Institute, North Carolina State University, 2620 Yarbrough Drive, Raleigh, NC, 27695, USA.
Angew Chem Int Ed Engl. 2018 Jul 9;57(28):8682-8686. doi: 10.1002/anie.201805078. Epub 2018 Jun 10.
Natural products have historically been a major source of antibiotics and therefore novel scaffolds are constantly of interest. The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogues to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.
天然产物一直是抗生素的主要来源，因此新型支架一直受到关注。脂氧恶唑烷酮类海洋天然产物，以其核心的不寻常的 4-恶唑烷酮杂环为代表，是一种新的抗菌发现的支架；然而，关于其作用机制和高亲脂性的问题可能减缓了后续研究。本文首次报道了脂氧恶唑烷酮 A 的全合成，合成了 15 个结构类似物，以探索其活性药效基团，并进行了初步的耐药性和作用机制研究。这些结果表明，4-恶唑烷酮是有价值的抗菌药物开发支架，并揭示了简化的先导化合物，以进一步优化。
