Abstract
A new series of 6-(hydroxyethyl)penems 2-substituted with amino acid-related side chains was synthesized. The nature of the amino acyl derivative proved to be crucial both from a synthetic point of view, as beta-lactam ring opening can compete with C-2 nucleophilic substitution, and for antibacterial activity. Primary amino acid amides emerged as the most suitable side chains for enhancing permeability through a Gram-negative outer membrane. In vitro activity of the new 2-[(aminoamido)methyl]penems 3a-u was influenced by the nature and position of the amide moiety, the ring size for cyclic amides, and the configuration of the amino acid. Compounds bearing amides derived from small N-methyl amino acids (such as 3a) or from cyclic amino acids (such as prolinamide 3p and 4-hydroxyprolinamide 3r) showed broad spectrum in vitro activity against both Gram-positive and Gram-negative microorganisms.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acids / chemistry
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / pharmacology
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Bacteria / drug effects*
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Enterococcus faecalis / drug effects
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Escherichia coli / drug effects
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Hydroxyproline / analogs & derivatives*
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Hydroxyproline / chemical synthesis
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Hydroxyproline / pharmacology
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Molecular Conformation
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Molecular Structure
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Penicillins / chemical synthesis*
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Penicillins / pharmacology
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Proline / analogs & derivatives*
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Proline / chemical synthesis
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Proline / pharmacology
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Pseudomonas aeruginosa / drug effects
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Staphylococcus aureus / drug effects
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Structure-Activity Relationship
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beta-Lactams
Substances
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2-((1-prolinamido)methyl)-6-(1-hydroxyethyl)penem-3-carboxylic acid
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2-((4-hydroxy-1-prolinamido)methyl)-6-(1-hydroxyethyl)penem-3-carboxylic acid
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2-((N-(2-acetamido)-N-methylamino)methyl)-6-(1-hydroxyethyl)penem-3-carboxylic acid
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Amino Acids
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Anti-Bacterial Agents
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Penicillins
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beta-Lactams
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Proline
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Hydroxyproline