Abstract
A novel series of fully synthetic 8-azatetracyclines was prepared and evaluated for antibacterial activity. Compounds were identified that overcome both efflux (tet(K)) and ribosomal protection (tet(M)) tetracycline resistance mechanisms and are active against Gram-positive and Gram-negative organisms. Two compounds were identified that exhibit comparable efficacy to marketed tetracyclines in in vivo models of bacterial infection.
MeSH terms
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Administration, Oral
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Animals
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology
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Aza Compounds / chemical synthesis*
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Aza Compounds / chemistry
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Aza Compounds / pharmacology
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Biological Availability
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Escherichia coli Infections / prevention & control
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Gram-Negative Bacteria / drug effects
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Gram-Positive Bacteria / drug effects
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Injections, Intravenous
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Mice
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Microbial Sensitivity Tests
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Rats
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Rats, Sprague-Dawley
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Sepsis / prevention & control
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Streptococcal Infections / prevention & control
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Structure-Activity Relationship
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Tetracycline Resistance / drug effects
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Tetracyclines / chemical synthesis*
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Tetracyclines / chemistry
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Tetracyclines / pharmacology
Substances
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6-demethyl-6-deoxy-7-(dimethylamino)-8-azatetracycline
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7-chloro-6-demethyl-6-deoxy-9-((3-(dimethylamino)-2,2-dimethylpropyl)amino)-8-azatetracycline
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Anti-Bacterial Agents
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Aza Compounds
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Tetracyclines