2. Academic Validation
  3. Discovery of novel pleuromutilin derivatives as potent antibacterial agents

Discovery of novel pleuromutilin derivatives as potent antibacterial agents

  • Eur J Med Chem. 2022 Jul 5;237:114403. doi: 10.1016/j.ejmech.2022.114403.
Yuhang Zhou 1,  Yunpeng Yi 2,  Jiangkun Wang 3,  Zheng Yang 4,  Qinqin Liu 4,  Wanxia Pu 4,  Ruofeng Shang 5
Affiliations

Affiliations

  • 1 Key Laboratory of New Animal Drug Project, Gansu Province/Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs/Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou, 730050, China. Electronic address: zhouyuhangcaas@163.com.
  • 2 Shandong Provincial Animal and Poultry Green Health Products Creation Engineering Laboratory, Institute of Poultry Science, Shandong Academy of Agricultural Science, 202 Gongyebeilu Jinan, 250023, Shandong, China. Electronic address: yiyp@foxmail.com.
  • 3 School of Basic Medical Sciences, Lanzhou University, 730000, Lanzhou, China.
  • 4 Key Laboratory of New Animal Drug Project, Gansu Province/Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs/Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou, 730050, China.
  • 5 Key Laboratory of New Animal Drug Project, Gansu Province/Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture and Rural Affairs/Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou, 730050, China. Electronic address: shangrf1974@163.com.
PMID: 35472849 DOI: 10.1016/j.ejmech.2022.114403
Abstract

Novel pleuromutilin derivatives with 3,4-dihydropyrimidin and pyrimidine moieties were designed, synthesized, and evaluated for their Antibacterial activities. Most of the synthesized derivatives, especially the compounds bearing the pyrimidine moieties, exhibited potent Antibacterial activities against methicillin-resistant Staphylococcus aureus BNCC 337371 (MRSA-337371), Staphylococcus aureus ATCC 25923 (S. aureus-25923) and methicillin-resistant Staphylococcus epidermidis ATCC 51625 (MRSE-51625). Compounds 5a, 5g and 5h exerted the excellent Antibacterial activities and selected to evaluate their Bacterial killing kinetics. Compound 5h displayed the highest Antibacterial activities with bacteriostatic activities against MRSA and further evaluated its efficacy in mouse systemic Infection. The results showed that compound 5h exhibited potent in vivo Antibacterial effects to significantly improve the survival rate of mice (ED50 = 16.14 mg/kg), reduce the Bacterial load and alleviate the pathological changes in the lungs of the affected mice. Furthermore, molecular docking studies revealed that the selected compounds successfully localized in the pocket of 50S ribosomal subunit and the formed hydrogen bonds were the main interaction.

Keywords

Antibacterial activity; In vivo efficacy; Molecular docking; Pleuromutilin derivatives; Synthesis.

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