Synthesis of novel 15-membered 8a-azahomoerythromycin A acylides: Consequences of structural modification at the C-3 and C-6 position on antibacterial activity

Dražen Pavlović, SCOTT DAVID KIMMINS, Stjepan Mutak

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

A novel series of 6-O-substituted 8a-aza-8a-homoerythromycin A 3-O-acylides has been discovered with potent activity against key respiratory pathogens, including those inducibly and constitutively resistant to erythromycin. The best compounds in this series 15na and 15nd showed activity comparable to telithromycin, especially against Haemophilus influenzae and constitutively MLSB-resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes. Furthermore, 15na exhibited a number of drug-like attributes including favorable pharmacokinetic properties and in vivo efficacy. For instance, 15na exhibited good oral bioavailability (average F = 42%) and demonstrated in vivo efficacy superior to telithromycin (1) against erythromycin-susceptible S. pneumoniae. As such, 15na has a significant potential for further development of this novel macrolide antibiotics class.

Original languageEnglish
Pages (from-to)210-224
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Volume125
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • Acylides
  • Antibacterial activity
  • Heck reaction
  • Macrolide antibiotics
  • Macrolide resistance
  • Structure-activity relationships

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