ACYLOXYMETHYL AS A DRUG PROTECTING GROUP, .3. TERTIARY O-AMIDOMETHYL ESTERS OF PENICILLIN-G - CHEMICAL HYDROLYSIS AND ANTIBACTERIAL ACTIVITY

Purpose. O-(N-alkylamido)methyl esters of penicillin G were studied as a new class of prodrugs. Methods. Their hydrolysis in aqueous buffers containing 20 % (v/v) of acetonitrile was investigated by HPLC. Resul ts. 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 involv ing rate-limiting iminium ion formation and penicillinoate expulsion. Penicillin G and the corresponding amide are the ultimate products det ected and isolated, indicating that beta-lactam ring opening is much s lower than ester hydrolysis. The O-(N-alkylamido)methyl esters of peni cillin G displayed similar in vitro antibacterial activity to penicill in G itself. Conclusions. Compared to the penicillin G derivatives, th e much higher stability of the O-(N-methylbenzamido)methyl benzoate, a cetate and valproate esters (which gave rise to a Bronsted beta(Ig) va lue of ca. -1) suggests that tertiary N-acyloxymethylamides may be use ful prodrugs for carboxylic acid drugs with pK(a) > 4.