PM3 study of reactivity of non-classical beta-lactam structures

Abstract

[eng] Various mechanisms for the alkaline hydrolysis of aza-beta-lactam (na), oxo-beta-lactam (oa) and thio-beta-lactam compounds (sa) were analysed on the basis of PM3 calculations in order to identify potential differences with classical beta-lactam antibiotics. Changes in the tetrahedral intermediate were studied via the cleavage of not only the bond between atoms at 7 and 4 as in classical beta-lactam antibiotics but also of that between those at 7 and 6, which was previously put forward as a plausible pathway for the hydrolysis of these compounds. Cleavage of the 7<br>6 bond was found to be the energetically more favourable pathway in the three compounds studied, both in the gas phase and in solution. Opening of the b-lactam ring at the 7<br>6 bond yields especially stable carbamates, which suggests a potential inhibitory action in serine-b-lactamases. Based on the computations, those hydrolysis products where the five-membered ring is opened by cleavage of the C5<br>S1 bond are highly stable.