Pii: S0166-1280(99)00250-x

Various mechanisms for the alkaline hydrolysis of aza-b-lactam (na), oxo-b-lactam (oa) and thio-b-lactam compounds (sa) were analysed on the basis of PM3 calculations in order to identify potential differences with classical b-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 b-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 7–6 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 7–6 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–S1 bond are highly stable. q 1999 Elsevier Science B.V. All rights reserved.