Synthesis of new sulfonylamido-penicillanic acid sulfones inhibitors of β-lactamases

Article abstract of DOI:10.7164/antibiotics.47.1041

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 β-lactamases suicide inhibitors by removal of the C3 ester protecting group. This synthetic strategy can give access to sulfonamido-penam sulfones bearing a variety of 6-amino side chain. These inhibitors inactivate the RTEM β-lactamase rapidly. The kinetics of inactivation are consistent with the partitioning of an acyl-enzyme 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.