2. Academic Validation
  3. Design, synthesis and structure-activity relationships of novel non-ketolides: 9-Oxime clarithromycin featured with seven-to thirteen-atom-length diamine linkers at 3-OH

Design, synthesis and structure-activity relationships of novel non-ketolides: 9-Oxime clarithromycin featured with seven-to thirteen-atom-length diamine linkers at 3-OH

  • Eur J Med Chem. 2024 Jun 25:276:116630. doi: 10.1016/j.ejmech.2024.116630.
Cong-Xuan Ma 1,  Wen-Tian Liu 1,  Xue-Meng Li 1,  Jing Ding 1,  Si-Meng Liu 1,  Feng Xue 2,  Yun Li 3,  Jian-Hua Liang 4
Affiliations

Affiliations

  • 1 Key Laboratory of Medicinal Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 102488, China.
  • 2 Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, 100034, China.
  • 3 Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, 100034, China. Electronic address: liyun19702@sina.com.
  • 4 Key Laboratory of Medicinal Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 102488, China. Electronic address: ljhbit@bit.edu.cn.
PMID: 38972081 DOI: 10.1016/j.ejmech.2024.116630
Abstract

We report here on the structure-activity relationships of hybrids combining 3-descladinosyl clarithromycin with quinolones linked by extended diamine connectors. Several hybrids, exemplified by 23Bc, 23Be, 23Bf, 26Be, and 30Bc, not only restored potency against inducibly resistant pathogens but also exhibited significantly enhanced activities against constitutively resistant strains of Staphylococcus pneumoniae and Staphylococcus pyogenes, which express high-level resistance independent of clarithromycin or erythromycin induction. Additionally, the novel hybrids showed susceptibility against Gram-negative Haemophilus influenzae. Notably, hybrid 23Be demonstrated dual modes of action by inhibiting both protein synthesis and DNA replication in vitro and in vivo. Given these promising characteristics, 23Be emerges as a potential candidate for the treatment of community-acquired Bacterial pneumonia.

Keywords

Ciprofloxacin; Erythromycin; Macrolide; Quinolone; Resistant bacteria; Ribosome.

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