ABSTRACT
Structure-activity relationships in a series of (5R)-6-triazolylmethylene penems with potent beta-lactamase inhibitory activity are described. In most cases, their in vitro synergistic activity with amoxycillin is superior to that of clavulanic acid, sulbactam and tazobactam (YTR 830). Against an Escherichia coli TEM-1 infection in mice, the compounds showed a broad range of potencies; an optimum polarity was found, however, which gave maximum potency.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Triazoles/chemical synthesis , beta-Lactamase Inhibitors , Amoxicillin/pharmacology , Animals , Anti-Bacterial Agents/pharmacology , Drug Synergism , Escherichia coli Infections/drug therapy , Humans , Mice , Microbial Sensitivity Tests , Structure-Activity Relationship , Triazoles/pharmacologyABSTRACT
Sodium (5RS)-Z-6-(substituted methylene)penem-3-carboxylates (3) are extremely potent inhibitors of bacterial beta-lactamases, but some members of this group of compounds are highly bound to human serum, while others are readily degraded by renal dehydropeptidase I enzyme. Consequently, the stability of a variety of 6-(substituted methylene)penems (3) to human kidney homogenate, their binding to human serum and their activity in a mouse infection model was investigated at an early stage, and were instrumental in the selection of the 1,2,3-triazolylmethylene derivatives (e.g. 3k) as a class of compounds worthy of further evaluation.
