Synthesis and preliminary biological evaluation of 3 '-substituted cephem sulfones as potential beta-lactamase inhibitors

3 ' -Substituted cephem sulfones, as well as the unsubstituted congener, we re synthesized and biologically evaluated as beta -lactamase inhibitors. So dium 3 ' -substituted cephalosporanate sulfones 4 and 5 were prepared start ing from 7-aminodeacetoxycephalosporanic acid (7-ADCA, 6) by a bromodeamina tion reaction, followed by reduction of the 7-halo derivative. Selective, r adical bromination at C-3 ' on the Delta (3)-isomer, followed by nucleophil ic substitution and then retroisomerization at Delta (2), afforded the requ ired derivatives. 3 ' -Unsubstituted and 3 ' -acetoxycephem sulfones 2 and 3 were prepared using routine chemistry. The 3 ' -substituted cephem sulfon e derivatives, evaluated as beta -lactamase inhibitors by IC50 determinatio ns, behave as weak inhibitors of the class D "oxacillinase" OXA1 from Esche richia coli and the class C beta -lactamase of Enterobacter cloacae P99. Co nversely, the 3 ' -unsubstituted cephem sulfone 2 was shown to be comparabl e to sulbactam and even more active than clavulanic acid against the latter enzyme. The activity of 2 against E. cloacae P99 was also greatly enhanced by prolonging the pre-incubation time. Considerations as to the mechanism of inhibition are also put forward.