1-Oxacephalosporins: enhancement of beta-lactam reactivity and antibacterial activity

The effect of replacement of sulfur in the cephem nucleus by oxygen upon the beta-lactamase stability, infrared carbonyl frequency of the beta-lactam ring, and antibacterial activity was investigated. The replacement reduced the stability of beta-lactam compounds to beta-lactamases, increased the IR frequencies, and enhanced the intrinsic antibacterial activity against bacterial strains without beta-lactamase. The instability of 1-oxacephalosporins to beta-lactamases, in other words, high reactivity to the enzymes, seemed to be due to the enhanced chemical reactivity of their beta-lactam rings which was indicated by their higher IR beta-lactam carbonyl frequencies. Based on a view that acylation of the enzyme by beta-lactam compounds occurred in both cases of beta-lactamase hydrolysis and target enzyme inhibition, the suggestion was made that one of the factors which conferred the higher intrinsic antibacterial activity on 1-oxacephalosporins was their high reactivity to the target enzyme(s), as was the case with beta-lactamases.