The chemistry and structure-activity relationships of C3-quaternary ammonium cephem antibiotics

The observation of a broad spectrum of antibacterial activity for cefpirome and for cefepime highlighted the benefits of combining a C3-quaternary ammonium substituent with the (Z)-2-(2-aminothiazol-4-yl)-2-methoxy-iminoacetamido side chain at C7. The quaternary nitrogen imparts beta-lactamase stability and improves both the cell penetration and the pharmacokinetic properties of these antibiotics. A variety of different quaternary ammonium substituents have been added, successive alterations in the groups attached to nitrogen have extended the activity of the fourth generation compounds. A number of different methods for attaching the quaternary ammonium group have been established, including the direct linkage to the C3-methylene, linkage via a C3-thiomethylene and also linkage via an alkenyl bridge. A number of different strategies have been developed for the preparation of these derivatives and these have been collated in this review. The beta-lactamase stability of fourth generation cephalosporins can be attributed to the formation of a transiently stable modified acyl-enzyme. The extent to which the modified acyl-enzyme contributes to the beta-lactamase stability is very much dependent on the leaving ability (nucleofugacity) of the C3-substituent. The influence of the quaternary ammonium substituents, on the formation of the modified acyl-enzyme, will be discussed.