Cephalosporins structures

Further, the discovery of 7-a-methoxy cephalosporins [5] from Streptomyces in 1971, carbapenems [6], thienamycin [7], clavulanic acid [8], sulbactum [9] as well as the totally synthetic oxapenems [10], oxacephams [11], and other bicyclic (3-lactams stimulated the search for novel antibiotics. More recent dedicated efforts to find new active molecules and modify the penicillin and cephalosporin structure have resulted in the discovery of simple monocyclic (3-lactams such as norcardicins and monobactams [12, 13]. Yet another dimension has been added to the (3-lactam research with the recent discovery of tricyclic (3-lactam antibiotics called trinems [14]. Thus, (3-lactam antibiotics in general can be classified into several groups based on their structures (Fig. 1). 

All cephalosporins found in nature (Tables 1 and 2) have the D-a-aminoadipic acid 7-acyl side chain (21). All of these compounds can be classified as having rather low specific activity. A substantial amount of the early work in the cephalosporin area was unsuccessfully directed toward replacing the aminoadipic acid side chain or modifying it appropriately by fermentation or enzymatic processes (6,22). A milestone in the development of cephalosporins occurred in 1960 with the discovery of a practical chemical process to remove the side chain to afford 7-ACA (1) (1). Several related processes were subsequently developed (22,23). The ready availability of 7-ACA opened the way to thousands of new semisynthetic cephalosporins. The cephalosporin structure offers more opportunities for chemical modification than does that of penicillins. There are two side chains that especially lend themselves to chemical manipulation the 7-acylamino and 3-acetoxymethyl substituents. 

Dunn GL. Ceftizoxime and other third-generation cephalosporins Structure activity relationships. J Antimicrob Chemother... 

The 3-acetoxymethyl group, and the A2-unsaturated center of the cephalosporin structure (461) are without parallel in penicillin, and the scope of modi-... 

Figure 1. Cephalosporin structures. Continued on next ] page.

From Baldo BA. Diagnosis of allergy to penicillins and cephalosporins. Structural and immunochemical considerations. Allergy Clin Immunol Int. 2000 12 206. Reprinted with permission fiom 2000 Hogrefe Huber Publishers (now Hogrefe Publishing). http //www. hogrefe.com... 

Cephalosporin Structure R,-CONH- COOH Inhibition (%) of IgE antibody binding by 500 nmol of cephalosporin with serum ... 

The concept of modeling in a computer a critical biochemical step in the mode of action of a drug has been shown to be illuminating. Noteworthy for their usefulness have been the transition state energy (TSE) and charge distributions at the p-lactam carbonyl as obtained from quantum mechanical calculations on cephalosporin structures. In effect, these computer-calculated indices reflect a compound s intrinsic activity, i.e.. 

Since modification at C-3 of the cephalosporin structure has led to derivatives with improved antibacterial activity, this area has received a great deal of attention. A key intermediate for C-3 modification is the aldehyde (65 e). For example, the 3,4-dicarboxylic acid (66) was obtained from (65) via a seven-step synthesis. The diacid in turn was converted into a number of C-3-modified derivatives, e.g. (67), (68). The dipolar iV-methylnitrone (69), resulting from the reaction of... 

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