Fidaxomicin (1, tiacumicin B, lipiarmycin A3) is a marketed antibiotic that is used in the treatment of Clostridium difficile infections. Based on the analysis of a cryo‐EM structure of fidaxomicin binding to its target enzyme (RNA‐polymerase), a cation‐π interaction of the aromatic moiety with an arginine residue was identified. Therefore, the variation of the substituents and concurrently changing the electronic properties of the aryl moiety represents an interesting strategy in the search for new fidaxomicin analogs. Herein, we report the first semisynthetic access to new fidaxomicin analogs with varying halogen substituents through a Pd‐catalyzed hydrodechlorination reaction. Subsequent iodination gave access to the first iodo‐fidaxomicin derivatives, which matched or improved antibacterial properties compared to fidaxomicin against Mycobacterium tuberculosis and Staphylococcus aureus ATCC 29213.

中文翻译：

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碘化非达米星抗生素的合成及生物学评价

非达霉素（1，tiacumicin B，lipiarmycin A3）是一种上市的抗生素，用于治疗艰难梭菌感染。根据对非达索霉素与目标酶（RNA聚合酶）结合的冷冻EM结构的分析，阳离子π鉴定了芳族部分与精氨酸残基的相互作用。因此，取代基的变化和同时改变芳基部分的电子性质代表了寻找新的非达索霉素类似物的有趣策略。本文中，我们报道了通过Pd催化的加氢脱氯反应，首次半合成获得具有不同卤素取代基的新的非达索霉素类似物。随后的碘化作用使人们获得了第一个碘代非达克星衍生物，该衍生物与非达克星相比对结核分枝杆菌和金黄色葡萄球菌ATCC 29213具有相同的抗菌性能或改善了抗菌性能。