PURPOSE: 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.
PURPOSE: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: Joe S Matarlo; Yang Lu; Fereidoon Daryaee; Taraneh Daryaee; Bela Ruzsicska; Stephen G Walker; Peter J Tonge Journal: ACS Infect Dis Date: 2016-03-07 Impact factor: 5.084
Authors: Morten Rohde; Niels M Rk; Anders E Håkansson; Klaus G Jensen; Henrik Pedersen; Tina Dige; Erling B J Rgensen; René Holm Journal: Results Pharma Sci Date: 2014-05-02