title: Acyloxymethyl as a drug protecting group. Part 7: Tertiary sulfonamidomethyl ester prodrugs of benzylpenicillin: chemical hydrolysis and anti-bacterial activity.
abstract: Tertiary sulfonamidomethyl esters of benzylpenicillin (4) were synthesised and evaluated as a new class of potential prodrugs for beta-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 beta-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 Brønsted beta1g value of -0.96 and suggesting that tertiary sulfonamidomethyl esters may be useful prodrugs for carboxylic acid drugs with pKa > 4.
authors.affiliation: Chemistry Department, The Open University, Milton Keynes, UK. j.n.iley@open.ac.uk
authors.forename: J
authors.initials: J
authors.lastname: Iley
authors.forename: H
authors.initials: H
authors.lastname: Barroso
authors.forename: R
authors.initials: R
authors.lastname: Moreira
authors.forename: F
authors.initials: F
authors.lastname: Lopes
authors.forename: T
authors.initials: T
authors.lastname: Calheiros
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010400:Penicillin G / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D010406:Penicillins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D004952:Esters; D010406:Penicillins; D011355:Prodrugs; D013449:Sulfonamides; D010400:Penicillin G