Acyloxymethyl as a drug protecting group. Part 7: Tertiary sulfonamidomethyl ester prodrugs of benzylpenicillin: Chemical hydrolysis and anti-bacterial activity

Tertiary sulfonamidomethyl esters of benzylpenicillin (4) were synthesised and evaluated as a new class of potential prodrugs for beta-lactam antibiot ics. 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 con sistent with a unimolecular mechanism involving rate-limiting iminium ion F ormation and penicillinoate expulsion. Benzylpenicillin and the correspondi ng sulfonamide are the ultimate products detected and isolated, indicating that beta-lactam ring opening is much slower than ester hydrolysis. As expe cted from the high reactivity, benzylpenicillin eaters (4) displayed simila r in vitro antibacterial activity to benzylpenicillin itself. Compared to t he benzylpenicillin derivatives, sulfonamidomethyl esters of benzoic, clofi bric and valproic acids display a much higher stability, giving rise to a B ronsted beta(Ig) value of -0.96 and suggesting that tertiary sulfonamidomet hyl esters may be useful prodrugs for carboxylic acid drugs with pK(a) > 4. (C) 2000 Elsevier Science Ltd. All rights reserved.