2-Substituted Penems with Amino Acid-Related Side Chains: Synthesis and Antibacterial Activity of a New Series of .beta.-Lactam Antibiotics

• Published in: Journal of medicinal chemistry Vol. 38; no. 21; pp. 4244 - 4256
• Main Authors: Altamura, Maria, Perrotta, Enzo, Sbraci, Piero, Pestellini, Vittorio, Arcamone, Federico, Cascio, Giuseppe, Lorenzi, Laura, Satta, Giuseppe, Morandotti, Grazia, Sperning, Roberta
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.10.1995; Amer Chemical Soc
• Subjects: Amino Acids - chemistry; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacteria - drug effects; beta-Lactams; Biological and medical sciences; Chemistry, Medicinal; Enterococcus faecalis - drug effects; Escherichia coli - drug effects; Hydroxyproline - analogs & derivatives; Hydroxyproline - chemical synthesis; Hydroxyproline - pharmacology; Life Sciences & Biomedicine; Medical sciences; Molecular Conformation; Molecular Structure; Penicillins - chemical synthesis; Penicillins - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Proline - analogs & derivatives; Proline - chemical synthesis; Proline - pharmacology; Pseudomonas aeruginosa - drug effects; Science & Technology; Staphylococcus aureus - drug effects; Structure-Activity Relationship; INVITRO ACTIVITY; EFFICIENT SYNTHESIS; ESTERS; CEPHALOSPORIN; PENICILLIN; Penicillin derivatives; α-Aminoacid; Side chain; Structure activity relation; Aminoamide; Secondary alcohol; Antibacterial agent; Chemical synthesis; In vitro; Pyrrole derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00021a013

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 p-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.