2. Academic Validation
  3. Discovery of novel thiazole-pleuromutilin derivatives with potent antibacterial activity

Discovery of novel thiazole-pleuromutilin derivatives with potent antibacterial activity

  • Eur J Med Chem. 2025 Apr 5:287:117374. doi: 10.1016/j.ejmech.2025.117374.
Xian-Long Qi 1,  He-Chao Zhang 1,  Xiao Xu 1,  Xi-Wang Liu 1,  Ya-Jun Yang 1,  Zhun Li 2,  Jian-Yong Li 3
Affiliations

Affiliations

  • 1 Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Science of Chinese Academy of Agricultural Sciences, Lanzhou, 730050, PR China.
  • 2 Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Science of Chinese Academy of Agricultural Sciences, Lanzhou, 730050, PR China. Electronic address: lizhun@caas.cn.
  • 3 Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Science of Chinese Academy of Agricultural Sciences, Lanzhou, 730050, PR China. Electronic address: lijianyong@caas.cn.
PMID: 39938411 DOI: 10.1016/j.ejmech.2025.117374
Abstract

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 μM). 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.

Keywords

Antibacterial activity; Pleuromutilin derivatives; Synthesis; Thiazole; Toxicity.

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