Fatty peptides VI. Penicillin and cephalosporin esters with increased lipophilic character

Abstract

Several series of methoxycarhonyl alkyl esters, 2b-d, 3b and 4b-d, with increased lipophilicity, were prepared by conjugating penicillin G, ampicillin and cefuroxime, respectively. The suitability of this type of ester linkage as a pro-drug linkage for the carboxylic acid group of β-lactam antibiotics was determined both in vitro and in vivo. Only one compound, the penicillin G conjugate 2b showed a weak activity in vitro against the sensitive Staphylococcus aureus strain (663E), Pseudomonas and clostridia. The remaining conjugates 2c, d, 3b and 4b-d were inactive. Conjugates 2b-c and 4b exhibited antibiotic activity against S. aureus 663E following subcutaneous administration in the mouse. The most active conjugates 2b and 4b were methyl octanoyl derivatives of penicillin G and cefuroxime. It can be assumed that the secondary alcohol ester linkage was cleaved in vivo to afford active, presumably the parent, antibiotic. The penicillin G conjugate 2b-d and the ampicillin conjugate 3b were orally active, conjugate 3b was more active than the parent ampicillin, and cefuroxime conjugates 4c and d were orally inactive. Conjugation of a lipidic moiety via a secondary alcohol ester linkage may improve the absorption of β-lactam antibiotics. There appeared to be a preference for short alkyl chains for oral and subcutaneous activity in this series of conjugates, therefore, it can be assumed that the longer alkyl chains in compounds 2d, 4c and d protect the ester bond from esterases.