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

• Published in: Journal of medicinal chemistry 2003-06, Vol.46 (13), p.2569-2571
• Main Authors: Sandanayaka, Vincent P, Prashad, Amar S, Yang, Youjun, Williamson, R. Thomas, Lin, Yang I, Mansour, Tarek S
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm034056q

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.