Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Finland.
Department of Chemistry, Faculty of Science, University of Helsinki, P.O. Box 55, 00014, Finland.
Eur J Med Chem. 2021 Feb 5;211:113002. doi: 10.1016/j.ejmech.2020.113002. Epub 2020 Nov 11.
N-aryl-oxazolidinones is a prominent family of antimicrobials used for treating infections caused by clinically prevalent Gram-positive bacteria. Recently, boron-containing compounds have displayed intriguing potential in the antibiotic discovery setting. Herein, we report the unprecedented introduction of a boron-containing moiety such as an aryl boronic acid in the external region of the oxazolidinone structure via a chemoselective acyl coupling reaction. As a result, we accessed a series of analogues with a distal aryl boronic pharmacophore on the oxazolidinone scaffold. We identified that a peripheric linear conformation coupled with freedom of rotation and no further substitution on the external aryl boronic ring, an amido linkage with hydrogen bonding character, in addition to a para-relative disposition between boronic group and linker, are the optimal combination of structural features in this series for antimicrobial activity. In comparison to linezolid, the analogue comprising all those features, compound 20b, displayed levels of antimicrobial activity augmented by an eight-fold to a thirty-two-fold against a panel of Gram-positive strains, and a near one hundred-fold against Escherichia coli JW5503, a Gram-negative mutant strain with a defective efflux capability.
N-芳基恶唑烷酮是一类重要的抗菌药物，用于治疗临床上常见的革兰氏阳性菌感染。最近，含硼化合物在抗生素发现领域显示出了引人注目的潜力。在此，我们通过选择性酰基偶联反应，在恶唑烷酮结构的外部区域引入了前所未有的硼原子，如芳基硼酸。由此，我们获得了一系列在恶唑烷酮骨架上带有远端芳基硼酸药效团的类似物。我们发现，外围线性构象与旋转自由度以及外部芳基硼酸环上无进一步取代、具有氢键性质的酰胺键，再加上硼酸基团和连接基团之间的对位相对位置，是该系列化合物具有抗菌活性的最佳结构特征组合。与利奈唑胺相比，包含所有这些特征的类似物 20b，对一系列革兰氏阳性菌株的抗菌活性增强了 8 倍至 32 倍，对革兰氏阴性突变株 Escherichia coli JW5503 的抗菌活性增强了近 100 倍，该突变株具有缺陷的外排能力。
