Cephalosporin 3-carboxyl-functionalized

Because the integrity of the dihydrothiazine ring and its C-4 carboxyl substituent is crucial to useful antimicrobial activity, reactions involving this part of the cephalosporin molecule are usually undesirable. The possibilities for sulfur oxidation or alkylation, substitution at C-2 which is adjacent to both sulfur and a double bond, double bond isomerization and addition reactions, and the influence of a free carboxylic acid must all be considered in designing reactions to selectively modify other cephalosporin functionalities. 

Many advances in organic chemistry involve making and using derivatives of carboxylic acids. Proteins are bonded by amide functional groups, and chemists have created synthetic amides that emulate the desirable properties of proteins. For example, the nylon in a climbing rope is a synthetic polyamide that emulates the protein in a spider s web. All the penicillin and cephalosporin antibiotics are amides that extend the antimicrobial properties of naturally occurring antibiotics. 

Further, cephaloridine with moderate acylating activity is one of the most nephrotoxic cephalosporins. It was speculated that this discrepancy may be due to the presence of the cationic nitrogen group near to the carboxyl group of cephaloridine this could limit cephaloridine access to the anionic targets and thus requiring high intracellular concentration to induce nephrotoxicity [67]. Whereas experimental evidence supports the concept that some p-lactams may induce acylation of mitochondrial substrate carries, httle is known about the functional consequences of acylation of other cellular proteins [67]. 

The concept, also called distal hydrolysis or the double prodrug concept, is illustrated by the use of 2-acyloxymethylbenzoic acids as amine protective functions, providing amides with the lability of esters (Figure 36.18a) and by the use of substituted vinyl esters [= (2-oxo-l,3-dioxol-yl)methyl esters] as lipophilic cascade carriers for carboxylic acid-containing drugs such as ampicillin or a-methyldopa or various cephalosporins (Figure 36.18b). 

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