Acyloxymethyl as a drug protecting group. Part 3. Tertiary O-amidomethyl esters of penicillin G: chemical hydrolysis and anti-bacterial activity.
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.
Moreira
R
R
CECF, Faculty of Pharmacy, University of Lisbon, Lisboa, Portugal.
Calheiros
T
T
Cabrita
J
J
Mendes
E
E
Pimentel
M
M
Iley
J
J
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*
D004952:Esters; D010406:Penicillins; D011355:Prodrugs; D010400:Penicillin G