Design, synthesis and structure-bactericidal activity relationships of novel 9-oxime ketolides and reductive epimers of acylides

Jing Chao Tian, Xu Han, Wei Lv, Ya Xin Li, Hui Wang, Bing Zhi Fan, Mark Cushman, Jian Hua Liang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Erythromycin was long viewed as a bacteriostatic agent. The erythromycin derivatives, 9-oxime ketolides have a species-specific bactericidal profile. Among them, the 3′-allyl version of the 9-oxime ketolide 1 (Ar = 3-quinolyl; 17a) is bactericidal against Streptococcus pneumoniae and Streptococcus pyogenes. In contrast, the 2-fluoro analogs of 1, 13a (Ar = 6-quinolyl), 13b (Ar = 3-quinolyl) and 24a (Ar = 4-isoquinolyl), show bactericidal activities against S. pneumoniae, Staphylococcus aureus and Moraxella catarrhalis, while the 2-fluoro analogs 13c (Ar = 3-aminopyridyl) and 24b (Ar = 3-carbamoylpyridyl) are only bactericidal against S. pneumoniae and Haemophilus influenzae. Reduction of the ketolides led to novel epiacylides, the 3-O-epimers of the acylides. Alteration of linker length (30b vs. 30a), 2-fluorination (33 vs. 30a) and incorporation of additional spacers at the 9-oxime or 6-OH (35, 40 vs. 30a) did not restore the epiacylides back to be as active as the acylide 31. Molecular docking suggested that epimerization at the 3-position reshapes the orientation of the 3-O-sidechain and leads to considerably weaker binding with bacterial ribosomes.

Original languageEnglish
Pages (from-to)1513-1524
Number of pages12
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number7
DOIs
Publication statusPublished - 2017

Keywords

  • Acylide
  • Bactericidal activity
  • Community-acquired bacterial pneumonia
  • Epimer
  • Erythromycin
  • Ketolide

Fingerprint

Dive into the research topics of 'Design, synthesis and structure-bactericidal activity relationships of novel 9-oxime ketolides and reductive epimers of acylides'. Together they form a unique fingerprint.

Cite this