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Total synthesis and antibacterial evaluation of Empetroxepins A and B and related analogs
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2022-08-26 , DOI: 10.1016/j.bmcl.2022.128955
Kyle E Murphy 1 , Marcia K Thacher 1 , Erin C Young 1 , Veronika Mojik 1 , Amanda L Wolfe 1
Affiliation  

Empetroxepins A and B, which are 10,11-dihydrodibenz[b,f]oxepins produced by the Black Crowberry (Empetrum nigrum), displayed weak anti-tubercular activity upon isolation, but have not been explored for antibiotic activity despite their molecular similarity to other phenolic antibacterial natural products. Herein we detail the first total synthesis of Empetroxepins A and B via a selective demethylation strategy and antibacterial structure activity relationship (SAR) study of the natural products and related analogs. Empetroxepin A was found to be weakly active against susceptible strains of Staphylococcus aureus (SA) and Bacillus subtilis (BS) with a minimum inhibitory concentration (MIC) of 256 μg/mL against both bacteria, whereas Empetroxepin B was found to be weakly active against only BS (MIC = 256 μg/mL). Neither natural product was active against Escherichia coli (EC). Antibiotic activity was improved through derivatization of the 10,11-dihydrodibenz[b,f]oxepin core with the best compound of the SAR series, 9-chloro-10,11-dihydrodibenzo[b,f]oxepine-2,3,4-triol, having MICs of 8 μg/mL, 16 μg/mL, and 256 μg/mL against SA, BS, and EC respectively.



中文翻译:

Empetroxepins A 和 B 及相关类似物的全合成和抗菌评价

Empetroxepins A 和 B 是由 Black Crowberry ( Empetrum nigrum ) 产生的10,11-二氢二苯并 [ b , f ]oxepins ,在分离时显示出较弱的抗结核活性,但尽管它们的分子相似性,但尚未探索其抗生素活性其他酚类抗菌天然产物。在此,我们通过选择性去甲基化策略和天然产物及相关类似物的抗菌结构活性关系 (SAR) 研究详细介绍了 Empetroxepins A 和 B 的首次全合成。Empetroxepin A 被发现对金黄色葡萄球菌(SA) 和枯草芽孢杆菌敏感菌株的活性较弱(BS) 对两种细菌的​​最小抑制浓度 (MIC) 为 256 μg/mL,而发现 Empetroxepin B 仅对 BS 具有弱活性 (MIC = 256 μg/mL)。两种天然产物均对大肠杆菌(EC)没有活性。通过 10,11-dihydrodibenz[ b , f ]oxepin 核心与 SAR 系列中最好的化合物 9-chloro-10,11-dihydrodibenzo[ b , f ]oxepine-2,3,4衍生化,提高了抗生素活性-三醇,对 SA、BS 和 EC 的 MIC 分别为 8 μg/mL、16 μg/mL 和 256 μg/mL。

更新日期:2022-08-31
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