Laws A, Page M
Dept. Chemical and Biological Sciences, University of Huddersfield, Queensgate, UK.
J Chemother. 1996 Feb;8 Suppl 2:7-22.
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-aminothiazole-4-yl)-2-methoxyiminoacetamido 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.
头孢匹罗和头孢吡肟具有广泛抗菌活性，这凸显了在C7位将C3-季铵取代基与(Z)-2-(2-氨基噻唑-4-基)-2-甲氧基亚氨基乙酰胺侧链相结合的益处。季氮赋予β-内酰胺酶稳定性，并改善了这些抗生素的细胞穿透性和药代动力学性质。已添加了多种不同的季铵取代基，氮原子上连接基团的连续改变扩展了第四代化合物的活性。已建立了多种连接季铵基团的不同方法，包括直接连接到C3-亚甲基、通过C3-硫亚甲基连接以及通过烯基桥连接。已开发出多种制备这些衍生物的不同策略，并在本综述中进行了整理。第四代头孢菌素的β-内酰胺酶稳定性可归因于形成了一种瞬时稳定的修饰酰基酶。修饰酰基酶对β-内酰胺酶稳定性的贡献程度很大程度上取决于C3-取代基的离去能力（亲核离去性）。将讨论季铵取代基对修饰酰基酶形成的影响。
