THE CHEMISTRY AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF C3-QUATERNARY AMMONIUM CEPHEM ANTIBIOTICS

The observation of a broad spectrum of antibacterial activity for cefp irome and for cefepime highlighted the benefits of combining a C3-quat ernary ammonium substituent with the )-2-(2-aminothiazol-4-yl)-2-metho xy-iminoacetamido side chain at C7. The quaternary nitrogen imparts be ta-lactamase stability and improves both the cell penetration and the pharmacokinetic properties of these antibiotics. A variety of differen t quaternary ammonium substituents have been added, successive alterat ions in the groups attached to nitrogen have extended the activity of the fourth generation compounds. A number of different methods for att aching 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 strateg ies have been developed for the preparation of these derivatives and t hese have been collated in this review. The beta-lactamase stability o f 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 ve ry much dependent on the leaving ability (nucleofugacity) of the C3-su bstituent. The influence of the quaternary ammonium substituents, on t he formation of the modified acyl-enzyme, will be discussed.