Synthesis and β-lactamase inhibitory activity of 6-fluoropenicillanic acids

• Published in: Bioorganic & medicinal chemistry 1993-12, Vol.1 (6), p.447-455
• Main Authors: Danelon, Gerardo O., Laborde, Maria, Mascaretti, Oreste A., Boggio, Suvana B., Roveri, Oscar A.
• Format: Article
• Language: English
• Subjects: Bacillus cereus - enzymology; beta-Lactamase Inhibitors; Magnetic Resonance Spectroscopy; Molecular Structure; Penicillanic Acid - chemical synthesis; Penicillanic Acid - chemistry; Penicillanic Acid - pharmacology; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)82155-0

The benzyl 6-fluoro-penicillanate sulfides 4a, 6a, 7a; and sulfones 6c, 7d were synthesized. The conversion to their free acids 4b, 4b, 6d, 7b, 7e and potassium salts 7c, 7f are described. These acids and salt 7c were evaluated as β- lactamase inhibitors using β-lactamase I from Bacillus cereus. The data indicate that substitution of the 6α-hydrogen by a 6α- fluorine atom on 6β-bromopenicillanic acid ( 1), leads to loss of β-lactamase inhibitory activity. In the case of the isomers 6β- and 6α-fluoropenicillanic acids the 6β-enantiomer proved to be considerably more potent. Potassium salts of 6β- fluoropenicillanate sulfide and sulfone were unstable in solid state and in water solution. The fragmentation of the sulfone in two parts in water solution is consistent with the hydrolytic behavior of the penicillanic acid sulfone ( 2) with 0.5 N NaOH. This article describe the structure activity relationships in a serie of fluorinated penicillin sulfides and sulfones as inhibitors of the β-lactamase I from Bacillus cereus.