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 mechanisms of hydrolysis of the ?-lactam isatin and its derivatives

The pH dependences of the rates of hydrolysis of isatin, its N-carboxymethyl derivative and its 5-nitro substituted analogues exhibit a complex behaviour, showing a first- and second-order dependence upon hydroxide ion concentration, as well as a pH-independent pathway. The pH dependence is interpreted in terms of the formation of tetrahedral intermediates in different protonic states which may break down to products via hydroxide ion, hydronium ion and water catalysed pathways. These -lactams are as reactive, or more reactive, than benzylpenicillin

An unexpected Mitsunobu reaction. A direct route to the 2,5-diazabicyclo[2.2.1]heptan-3-one skeleton as a γ-lactam mimic of β-lactam antibiotics

Treatment of anilides of N-protected (2S,4R)-4-hydroxyproline, e.g. 1, with thioacetic acid under Mitsunobu conditions gives, unexpectedly, 2,5-diazabicyclo[2.2.1]heptan-3-ones, e.g. 2, the products of intramolecular cyclisation. However, the less acidic N-benzylamides of these proline derivatives, e.g. 7, are not sufficiently acidic and the hydrazido anion generated in the Mitsunobu reaction displaces the activated hydroxy group in an intermolecular reaction to give 8. The bicyclic -lactams are potential analogues of the -lactam antibiotics and suitable derivatives 9, 10, 11 and 12 are found to be competitive inhibitors of class A and C -lactamases, with Ki as low as 70