title: Acyloxymethyl as a drug protecting group. Part 3. Tertiary O-amidomethyl esters of penicillin G: chemical hydrolysis and anti-bacterial activity.
abstract: OBJECTIVE
  O-(N-alkylamido)methyl esters of penicillin G were studied as a new class of prodrugs.
  
  
  METHODS
  The hydrolysis in aqueous buffers containing 20 % (v/v) of acetonitrile was investigated by HPLC.
  
  
  RESULTS
  A U-shaped pH-rate profile was seen with a pH-independent process extending from pH ca. 2 to pH ca. 10. This pathway is characterised by kinetic data that are consistent with a unimolecular mechanism involving rate-limiting iminium ion formation and penicillinoate expulsion. Penicillin G and the corresponding amide are the ultimate products detected and isolated, indicating that beta-lactam ring opening is much slower than ester hydrolysis. The O-(N-alkylamido)methyl esters of penicillin G displayed similar in vitro antibacterial activity to penicillin G itself.
  
  
  CONCLUSIONS
  Compared to the penicillin G derivatives, the much higher stability of the O-(N-methylbenzamido)methyl benzoate, acetate and valproate esters (which gave rise to a Bronsted Beta 1g value of ca. -1) suggests that tertiary N-acyloxymethylamides may be useful prodrugs for carboxylic acid drugs with pKa > 4.
authors.affiliation: CECF, Faculty of Pharmacy, University of Lisbon, Lisboa, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Moreira
authors.forename: T
authors.initials: T
authors.lastname: Calheiros
authors.forename: J
authors.initials: J
authors.lastname: Cabrita
authors.forename: E
authors.initials: E
authors.lastname: Mendes
authors.forename: M
authors.initials: M
authors.lastname: Pimentel
authors.forename: J
authors.initials: J
authors.lastname: Iley
mesh_terms: D000215:Acylation; D002384:Catalysis; D004355:Drug Stability; D004952:Esters; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008745:Methylation; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010400:Penicillin G / Q000378:metabolism / Q000494:pharmacology*; D010406:Penicillins / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004952:Esters; D010406:Penicillins; D011355:Prodrugs; D010400:Penicillin G