Anhydrolide macrolides. 1. Synthesis and antibacterial activity of 2,3-anhydro-6-O-methyl 11,12-carbamate erythromycin A analogues.
A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11, 12-carbamate analogues have been synthesized and evaluated for antibacterial activity. These compounds were found to be potent antibacterial agents against Gram-positive organisms in vitro, many having MIC values below 1 microg/mL for the macrolide-susceptible Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae, as well as improved activity compared to erythromycin A against the inducibly MLS (macrolide, lincosamide, and streptogramin B)-resistant organisms. Structure-activity studies revealed that arylalkyl carbamates with two and four carbon atoms between the aromatic moiety and carbamate nitrogen have the best in vitro activity. All of the C-10 epi analogues evaluated were found to have substantially less activity than the corresponding natural C-10 isomer. Several analogues demonstrated moderate antibacterial activity against the constitutively resistant S.aureus A-5278, S. pneumoniae5979, and S.pyogenes 930. However, despite potent in vitro activity, these analogues showed only moderate in vivo activity in mouse protection studies.
Elliott
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Pharmaceutical Products Research Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA. richard_l_elliott@groton.pfizer.com
Pireh
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Griesgraber
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Nilius
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Ewing
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Bui
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Raney
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Flamm
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Kim
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Henry
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Chu
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Plattner
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Or
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D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017291:Clarithromycin / Q000737:chemistry / Q000494:pharmacology; D015169:Colony Count, Microbial; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D004917:Erythromycin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006193:Haemophilus influenzae / Q000187:drug effects; D055231:Lincosamides; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D011008:Pneumococcal Infections / Q000517:prevention & control; D013203:Staphylococcal Infections / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship; D014769:Virginiamycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D002219:Carbamates; D055231:Lincosamides; D018942:Macrolides; D014769:Virginiamycin; D004917:Erythromycin; D017291:Clarithromycin