2-Substituted penems with amino acid-related side chains: synthesis and antibacterial activity of a new series of beta-lactam antibiotics.
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.
D000596:Amino Acids / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006909:Hydroxyproline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D010406:Penicillins / Q000138:chemical synthesis* / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D047090:beta-Lactams
C096259:2-((1-prolinamido)methyl)-6-(1-hydroxyethyl)penem-3-carboxylic acid; C096261:2-((4-hydroxy-1-prolinamido)methyl)-6-(1-hydroxyethyl)penem-3-carboxylic acid; C096257:2-((N-(2-acetamido)-N-methylamino)methyl)-6-(1-hydroxyethyl)penem-3-carboxylic acid; D000596:Amino Acids; D000900:Anti-Bacterial Agents; D010406:Penicillins; D047090:beta-Lactams; D011392:Proline; D006909:Hydroxyproline