title: Lipidic peptides. V: Penicillin and cephalosporin acid conjugates with increased lipophilic character.
abstract: 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.
authors.affiliation: School of Pharmacy, University of London, U.K.
authors.forename: R A
authors.initials: RA
authors.lastname: Hughes
authors.forename: I
authors.initials: I
authors.lastname: Toth
authors.forename: P
authors.initials: P
authors.lastname: Ward
authors.forename: A M
authors.initials: AM
authors.lastname: McColm
authors.forename: D M
authors.initials: DM
authors.lastname: Cox
authors.forename: G J
authors.initials: GJ
authors.lastname: Anderson
authors.forename: W A
authors.initials: WA
authors.lastname: Gibbons
mesh_terms: 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
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D010406:Penicillins; D010455:Peptides