Desosamines of azithromycin (AZM) and clarithromycin (CLA) were modified by N‐alkylation or nucleophilic substitution at the carbonyl/CuAAC sequence. Biological studies revealed a higher antibacterial potency of quaternary N‐alkylammonium bromides of CLA as compared to AZM. SAR studies of CLA salts, including biological, conformation and molecular‐docking analysis, enriched by physicochemical parameters, showed the importance of less bulky and unsaturated substituent for an efficient docking mode at the ribosomal tunnel and good antibacterial potency against clinical and standard Streptococcus pneumoniae and Streptococcus pyogenes strains (MICs 0.25 or 0.5 μg/mL). These CLA salts also have an at least threefold lower cytotoxicity than reference antibiotics at comparable antibacterial activity against the S. pneumoniae clinical strain. Differences in antibacterial effects noted for AZM and CLA salts bearing less bulky N‐substituents can be better understood when their binding modes in the ribosomal tunnel are considered rather than their common low lipophilicity and excellent water solubility.

中文翻译：

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14元和15元内酯大环内酯类的去氨中的新N-烷基铵和碳酸三唑衍生物的合成及抗菌活性。

阿奇霉素（AZM）和克拉霉素（CLA）的去氨胺通过N-烷基化或在羰基/ CuAAC序列上的亲核取代进行修饰。生物学研究表明，与AZM相比，CLA的季烷基N烷基溴化铵具有更高的抗菌效力。CLA盐的SAR研究包括生物学，构象和分子对接分析，并通过理化参数进行了丰富的研究，结果表明，体积小和不饱和取代基对于在核糖体隧道中有效对接方式以及对临床和标准肺炎链球菌和化脓性链球菌菌株（MIC 0.25或0.5μg/ mL）。在对肺炎链球菌临床菌株具有相当的抗菌活性时，这些CLA盐的细胞毒性也比参考抗生素低至少三倍。当考虑它们在核糖体通道中的结合模式，而不是通常的低亲脂性和优异的水溶性时，可以更好地理解带有较小体积N取代基的AZM和CLA盐在抗菌作用上的差异。