Anhydrolide Macrolides. 2. Synthesis and Antibacterial Activity of 2,3-Anhydro-6-O-methyl 11,12-Carbazate Erythromycin A Analogues

A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11,12-cyclic carbazate analogues was prepared and evaluated for antibacterial activity. These 2,3-anhydro macrolides were found to be potent antibacterial agents in vitro against macrolide-susceptible organisms including Staphylococcus...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1998-05, Vol.41 (10), p.1660-1670
Main Authors: Griesgraber, George, Kramer, Mark J, Elliott, Richard L, Nilius, Angela M, Ewing, Patty J, Raney, Patti M, Bui, Mai-Ha, Flamm, Robert K, Chu, Daniel T. W, Plattner, Jacob J, Or, Yat Sun
Format: Article
Language:English
Subjects:
Animals
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Biological and medical sciences
Clarithromycin - pharmacology
Drug Evaluation, Preclinical
Drug Resistance, Microbial
Drug Resistance, Multiple
Erythromycin - analogs & derivatives
Erythromycin - chemical synthesis
Erythromycin - chemistry
Erythromycin - pharmacology
Lincosamides
Macrolides - pharmacology
Medical sciences
Mice
Pharmacology. Drug treatments
Pneumococcal Infections - prevention & control
Staphylococcal Infections - prevention & control
Staphylococcus aureus - drug effects
Streptococcus pneumoniae - drug effects
Streptococcus pyogenes - drug effects
Structure-Activity Relationship
Virginiamycin - pharmacology
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Summary:A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11,12-cyclic carbazate analogues was prepared and evaluated for antibacterial activity. These 2,3-anhydro macrolides were found to be potent antibacterial agents in vitro against macrolide-susceptible organisms including Staphylococcus aureus 6538P, Streptococcus pyogenes EES61, and Streptococcus pneumoniae ATCC6303. These compounds were also very active against some organisms that show macrolide resistance (S. aureus A5177, S. pyogenes PIU2584, and S. pneumoniae 5649). The compounds generally showed poor activity against organisms with constitutive MLS resistance. Selected compounds were evaluated in vivo in mouse protection studies. Although most of the compounds tested in vivo showed poor efficacy, two compounds, 38 and 57, were more active than clarithromycin against S. pneumoniae ATCC6303.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm970548p