Orally active esters of cephalosporin antibiotics. 3. Synthesis and biological properties of aminoacyloxymethyl esters of 7-[D(-)-mandelamido]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-3-cephem-4-carboxylic acid.

The synthesis of six amino acid acyloxymethyl esters of cefamandole (1), a semisynthetic broad-spectrum cephalosporin antibiotic, is described. These esters were examined as potentially useful orally active antibiotic prodrugs. When tested for oral efficacy against Streptococcus pyogenes C203 in mouse protection tests, the esters were not notably more active than lithium cefamandole. Further studies demonstrated that significant blood and urine levels of 1 were not obtained after dosing 2a, 2b, and 2f orally at 17 mg/kg in mice. A study of the stability to chemical hydrolysis and the possible relationship of hydrolysis to the lack of oral absorption of these esters is also presented.