TY - JOUR
T1 - Acyloxymethyl as a drug protecting group. Part 7
T2 - Tertiary sulfonamidomethyl ester prodrugs of benzylpenicillin: Chemical hydrolysis and anti-bacterial activity
AU - Iley, Jim
AU - Barroso, Helena
AU - Moreira, Rui
AU - Lopes, Francisca
AU - Calheiros, Teresa
N1 - Funding Information:
This work was supported by Junta Nacional de Investigação Cientı́fica e Tecnológica (Portugal) under the contract PBIC/SAU/1546/92.
PY - 2000/7
Y1 - 2000/7
N2 - Tertiary sulfonamidomethyl esters of benzylpenicillin (4) were synthesised and evaluated as a new class of potential prodrugs for β-lactam antibiotics. Their hydrolysis in aqueous buffers was studied by HPLC and reveal a U-shaped pH-rate profile with a pH-independent process extending from ca. pH 2 to ca. pH 10. This pathway is characterised by kinetic data that are consistent with a unimolecular mechanism involving rate-limiting iminium ion formation and penicillinoate expulsion. Benzylpenicillin and the corresponding sulfonamide are the ultimate products detected and isolated, indicating that β-lactam ring opening is much slower than ester hydrolysis. As expected from the high reactivity, benzylpenicillin esters (4) displayed similar in vitro antibacterial activity to benzylpenicillin itself. Compared to the benzylpenicillin derivatives, sulfonamidomethyl esters of benzoic, clofibric and valproic acids display a much higher stability, giving rise to a Bronsted β(lg) value of -0.96 and suggesting that tertiary sulfonamidomethyl esters may be useful prodrugs for carboxylic acid drugs with pK(a)>4. Copyright (C) 2000 Elsevier Science Ltd.
AB - Tertiary sulfonamidomethyl esters of benzylpenicillin (4) were synthesised and evaluated as a new class of potential prodrugs for β-lactam antibiotics. Their hydrolysis in aqueous buffers was studied by HPLC and reveal a U-shaped pH-rate profile with a pH-independent process extending from ca. pH 2 to ca. pH 10. This pathway is characterised by kinetic data that are consistent with a unimolecular mechanism involving rate-limiting iminium ion formation and penicillinoate expulsion. Benzylpenicillin and the corresponding sulfonamide are the ultimate products detected and isolated, indicating that β-lactam ring opening is much slower than ester hydrolysis. As expected from the high reactivity, benzylpenicillin esters (4) displayed similar in vitro antibacterial activity to benzylpenicillin itself. Compared to the benzylpenicillin derivatives, sulfonamidomethyl esters of benzoic, clofibric and valproic acids display a much higher stability, giving rise to a Bronsted β(lg) value of -0.96 and suggesting that tertiary sulfonamidomethyl esters may be useful prodrugs for carboxylic acid drugs with pK(a)>4. Copyright (C) 2000 Elsevier Science Ltd.
UR - http://www.scopus.com/inward/record.url?scp=0033936572&partnerID=8YFLogxK
U2 - 10.1016/S0968-0896(00)00099-7
DO - 10.1016/S0968-0896(00)00099-7
M3 - Article
C2 - 10976510
AN - SCOPUS:0033936572
SN - 0968-0896
VL - 8
SP - 1629
EP - 1636
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 7
ER -