Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-ß-lactamase IMP-1.

There are currently no clinically available inhibitors of metallo-ß-lactamases (MBLs). These enzymes confer resistance to bacteria against a broad range of commonly used ß-lactam antibiotics, and are produced by an increasing number of bacterial pathogens. In this study, several thiol derivatives of l-amino acids were designed and synthesized, and their inhibitory effects against the metallo-ß-lactamase IMP-1 (subclass B1) were investigated. The most potent compound, derived from l-tyrosine, exhibited competitive inhibition, with a Ki of 86 nM. The ability of this compound to render MBL-expressing bacteria susceptible to imipenem was examined. Reductions in MIC values up to 5.2-fold were observed.

Captopril analogues as metallo-ß-lactamase inhibitors.

A number of captopril analogues were synthesised and tested as inhibitors of the metallo-ß-lactamase IMP-1. Structure-activity studies showed that the methyl group was unimportant for activity, and that the potencies of these inhibitors could be best improved by shortening the length of the mercaptoalkanoyl side-chain. Replacing the thiol group with a carboxylic acid led to complete loss of activity, and extending the length of the carboxylate group led to decreased potency. Good activity could be maintained by substituting the proline ring with pipecolic acid.

Synthesis of a series of carbon-14 labeled tetrahydropyrido[4,3-d]pyrimidin-4(3H)-ones.

A series of tetrahydropyrido[4,3-d]pyrimidin-4(3H)-ones labeled with carbon-14 in the 2-position of pyrimidinone moiety were prepared as part of a 3-step sequence from benz[amidino-(14) C]amidine hydrochloride as a key synthetic intermediate.