Spirocyclopropyl β-Lactams as Mechanism-Based Inhibitors of Serine β-Lactamases. Synthesis by Rhodium-Catalyzed Cyclopropanation of 6-Diazopenicillanate Sulfone

Class A−class C mechanism-based β-lactamase inhibitors were designed on the basis of the intermediacy of an oxycarbenium species capable of cross-linking with amino acids residues in the active site. Penams 24 and 27 were very potent against AmpC in vitro. The MIC values of 24 in combination with pi...

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Veröffentlicht in:	Journal of medicinal chemistry 2003-06, Vol.46 (13), p.2569-2571
Hauptverfasser:	Sandanayaka, Vincent P, Prashad, Amar S, Yang, Youjun, Williamson, R. Thomas, Lin, Yang I, Mansour, Tarek S
Format:	Artikel
Sprache:	eng
Schlagworte:	Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Bacterial Proteins beta-Lactamase Inhibitors beta-Lactamases - chemistry beta-Lactams - chemical synthesis beta-Lactams - chemistry beta-Lactams - pharmacology Biological and medical sciences Catalysis Crystallography, X-Ray Cyclopropanes - chemical synthesis Cyclopropanes - chemistry Cyclopropanes - pharmacology Diazonium Compounds - chemistry Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Escherichia coli - drug effects Medical sciences Microbial Sensitivity Tests Models, Molecular Pharmacology. Drug treatments Pseudomonas aeruginosa - drug effects Rhodium Serine - chemistry Serratia marcescens - drug effects Spiro Compounds - chemical synthesis Spiro Compounds - chemistry Spiro Compounds - pharmacology Structure-Activity Relationship Sulbactam - analogs & derivatives Sulbactam - chemistry
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Beschreibung
Zusammenfassung:	Class A−class C mechanism-based β-lactamase inhibitors were designed on the basis of the intermediacy of an oxycarbenium species capable of cross-linking with amino acids residues in the active site. Penams 24 and 27 were very potent against AmpC in vitro. The MIC values of 24 in combination with piperacillin against class A and class C producing organisms showed improvement over clinically used tazobactam.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm034056q