Synthesis and antibacterial evaluation of novel 4 double prime -glycyl linked quinolyl-azithromycins with potent activity against macrolide-resistant pathogens

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 6; pp. 1255 - 1267
• Main Authors: Pavlovic, Drazen, Mutak, Stjepan
• Format: Journal Article
• Language: English
• Published: 15-03-2016
• Subjects: Haemophilus influenzae; Moraxella catarrhalis; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes
• ISSN: 0968-0896
• DOI: 10.1016/j.bmc.2016.01.055

A new azithromycin-based series of antibacterial macrolones is reported, which features the use of a 4 double prime -ester linked glycin for tethering the quinolone side chain to the macrolide scaffold. Among the analogs prepared, compounds 9e and 22f with a quinolon-6-yl moiety were found to have potent and well-balanced activity against clinically important respiratory tract pathogens, including erythromycin-susceptible and MLS sub(B) resistant strains of Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae. In addition, potential lead compounds 9e and 22f demonstrated outstanding levels of activity against Moraxella catarrhalis and inducibly MLS sub(B) resistant Staphylococcus aureus. The best member of this series 22f rivals or exceeds, in potency, some of the most active ketolide antibacterial agents known today, such as telithromycin and cethromycin.