Imide and isatin derivatives as β-lactam mimics of β-lactam antibiotics

Activated γ-lactams, which are derivatives of succinimide, phthalimide and isatin with suitable elements of molecular recognition, have been synthesised as mimics of the ß-lactam antibiotics and their chemical and biological reactivity determined

The thiol catalysed hydrolysis of cephalosporins and possible rate-limiting amine anion expulsion

The rates of thiolysis of cephalosporins were investigated by high-performance liquid chromatography and 1H NMR spectroscopy. Thiols catalyse the hydrolysis through the formation of a thioester intermediate and the catalytically reactive form of the thiol is the thiolate anion. Variation of nucleophilic reactivity by changing the basicity of the thiolate anion generates a Brønsted nuc value of 1.22 with cephaloridine, indicating that the breakdown of the tetrahedral intermediate is the rate-limiting step. The effect of C3 substituents on the rate of thiolysis of cephalosporins generates a large Hammett of ca 12, which is compatible with C - N bond fission occurring without protonation of the -lactam nitrogen. Solvent kinetic isotope effects kH2O/kD2O of ca 1.1 also indicate that solvent water probably does not act as a general acid catalyst facilitating breakdown of the tetrahedral intermediate by protonating the departing amine. Copyright © 2004 John Wiley & Sons, Ltd

Thiol-catalysed hydrolysis of benzylpenicillin

Thiolysis of benzylpenicillin has been investigated by HPLC and 1H-NMR techniques. Thiols catalyse the hydrolysis of benzylpenicillin through the formation of a thioester intermediate. The catalytically reactive form of the thiol has been demonstrated to be the thiolate anion. Variation of reactivity with changing basicity of the thiolate anion generates a Brønsted nuc value of 0.96, indicating that the breakdown of the tetrahedral intermediate is the rate-limiting step, as occurs in aminolysis and alcoholysis. Solvent kinetic isotope effects of 2.2–2.4 indicate that the solvent, water, probably acts as a general acid catalyst in the breakdown of the tetrahedral intermediate. PM3 theoretical calculations support the proposal that breakdown of the tetrahedral intermediate is rate-limiting. The experimental activation energies for the thiolysis of benzylpenicillin vary from 6.9 to 10.4 kcal mol–