Discovery of novel thiazole-pleuromutilin derivatives with potent antibacterial activity

文献类型： 外文期刊

第一作者： Qi, Xian-Long

作者： Qi, Xian-Long;Zhang, He-Chao;Xu, Xiao;Liu, Xi-Wang;Yang, Ya-Jun;Li, Zhun;Li, Jian-Yong

作者机构：

关键词： Pleuromutilin derivatives; Thiazole; Synthesis; Antibacterial activity; Toxicity

期刊名称：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：5.9； 五年影响因子：6.4 ）

ISSN： 0223-5234

年卷期： 2025 年 287 卷

页码：

收录情况： SCI

摘要： A series of novel thiazole-pleuromutilin derivatives were designed and synthesized, and their antibacterial activities were evaluated. Most of the synthesized derivatives showed good activity against Gram-positive bacteria, among which compound h19 was more prominent and had the strongest antibacterial activity against MRSA. Compound h19 was selected for further evaluation of bacterial time-kill kinetics, and the results demonstrated its highly promising efficacy in inhibiting MRSA growth. Moreover, h19 exhibited a superior post-antibiotic effect (PAE) value and a lower possibility for bacterial resistance development compared to tiamulin. Docking studies demonstrated the strong affinity of h19 for the 50S ribosomal subunit with a binding free energy of -10.6 kcal/ mol. The cytotoxic assay indicated that h19 had low cytotoxicity on both HEK293T and HepG2 cells (IC50 > 200 mu M). In MRSA systemic-infected mouse model, h19 improved survival rates, reduced the bacterial load, and alleviated pathological changes in the lungs of the infected mice, which exhibited a more potent antibacterial efficacy compared to tiamulin. Compound h19 also displayed low oral toxicity with an LD50 value more than 2000 mg/kg.

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