Synthesis of new sulfonylamido-penicillanic acid sulfones inhibitors of beta-lactamases.
Three new sulfonylamido-penicillanic acid sulfones have been prepared by reaction of 6-aminopenicillanic esters with the monoester or monoamide derivatives obtained in nucleophilic substitution reactions by alcohol or aniline on the carboxyl chloride function of sulfoacetic dichloride followed by oxidation. These penicillin sulfones are converted to beta-lactamases suicide inhibitors by removal of the C3 ester protecting group. This synthetic strategy can give access to sulfonamidopenam sulfones bearing a variety of 6-amino side chain. These inhibitors inactivate the RTEM beta-lactamase rapidly. The kinetics of inactivation are consistent with the partitioning of an acylenzyme intermediate between two main pathways: regeneration of free enzyme and irreversible inactivation, little transient inactivation is observed. A slow inhibition by the product of enzymatic hydrolysis of the sulfones is also observed.
Vanwetswinkel
S
S
Laboratoire de Biochimie Physique et des Biopolymères, Université catholique de Louvain, Belgium.
Fastrez
J
J
Marchand-Brynaert
J
J
D019818:Clavulanic Acid; D002969:Clavulanic Acids / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D015394:Molecular Structure; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013407:Sulbactam / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013450:Sulfones / Q000737:chemistry; D065093:beta-Lactamase Inhibitors
C089897:6-((4-nitrobenzyloxycarbonyl)methylsulfonamido)penicillanic acid sulfone; C089898:6-((anilinocarbonyl)methylsulfonamido)penicillanic acid sulfone; C089899:6-((carboxy)methylsulfonamido)penicillanic acid sulfone; D002969:Clavulanic Acids; D013449:Sulfonamides; D013450:Sulfones; D065093:beta-Lactamase Inhibitors; D019818:Clavulanic Acid; D010397:Penicillanic Acid; D013407:Sulbactam