Haney Brittney A, Schrank Cassandra L, Wuest William M
Department of Chemistry, Emory University, 30322, United States.
Tetrahedron Lett. 2021 Jan 5;62. doi: 10.1016/j.tetlet.2020.152667. Epub 2020 Nov 16.
Our continued synthetic interest in this class of retinoids, CD437 and its analogs, against methicillin-resistant (MRSA) has brought us to explore further isosteric substitutions within the scaffold. Although our previous findings have shown promising activity against gram-positive pathogens, their therapeutic viability remained an issue. Specifically, through preliminary analysis, our best performing compound, analog 2, displayed low solubility within serum as well as high affinity for retinoid binding proteins with a concentration dependent relationship. To circumvent this issue, we proposed a class of analogs containing an azaborine substitution in place of the naphthalene moiety. Azaborines have a nitrogen-boron bond substituting a carbon-carbon double bond that alters the electronics of the parent scaffold. This motif has been explored successfully in cancer research but to the best of our knowledge has yet to be applied to antibiotics. Herein, we describe the synthesis of the desired analogs, antimicrobial activity, and surprising physiochemical properties.
我们对这类维甲酸（CD437及其类似物）抗耐甲氧西林金黄色葡萄球菌（MRSA）的持续合成兴趣促使我们进一步探索该骨架内的等排取代。尽管我们之前的研究结果显示对革兰氏阳性病原体具有有前景的活性，但其治疗可行性仍是一个问题。具体而言，通过初步分析，我们表现最佳的化合物——类似物2，在血清中溶解度低，且对维甲酸结合蛋白具有高亲和力，呈浓度依赖性关系。为解决这个问题，我们提出了一类用氮杂硼苯取代萘部分的类似物。氮杂硼苯具有一个氮 - 硼键取代了碳 - 碳双键，这改变了母体骨架的电子性质。这个基序已在癌症研究中成功探索，但据我们所知尚未应用于抗生素。在此，我们描述了所需类似物的合成、抗菌活性以及令人惊讶的物理化学性质。
