Lipidic peptides. V: Penicillin and cephalosporin acid conjugates with increased lipophilic character.
Lipophilic, double-ester derivatives of beta-lactam antibiotics with methylene, ethylene, and propylene spacers were prepared by crown-ether-assisted coupling of halogenoalkyl esters of 2-(tert-butoxycarbonylamino)decanoic acid to either penicillin G or cefuroxime. The hydroxyethyl ester of penicillin G and the tert-butoxypropyl ester of cefuroxime were also prepared. The lipophilic, double-ester conjugates, the hydroxyethyl ester of penicillin G, and the tert-butoxypropyl ester of cefuroxime showed weak or no antibiotic activity in vitro, as expected. The lipophilic penicillin G conjugates and the tert-butoxypropyl ester of cefuroxime were active in vivo against a nonpenicillinase-producing strain of Staphylococcus aureus after subcutaneous administration. The penicillin G double ester with propylene spacer and the tert-butoxypropyl ester of cefuroxime were inactive in vitro, a fact indicating that both compounds were hydrolyzed in vivo, as desired. After oral administration, the lipophilic, double-ester conjugate of penicillin G with methylene spacer and the tert-butoxypropyl ester of cefuroxime were active.
Hughes
R A
RA
School of Pharmacy, University of London, U.K.
Toth
I
I
Ward
P
P
McColm
A M
AM
Cox
D M
DM
Anderson
G J
GJ
Gibbons
W A
WA
D000284:Administration, Oral; D000596:Amino Acids / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D010406:Penicillins / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D010406:Penicillins; D010455:Peptides