6-(SUBSTITUTED METHYLENE)PENEMS, POTENT BROAD SPECTRUM INHIBITORS OF BACTERIAL β-LACTAMASE

IV. KIDNEY STABILITY, SERUM BINDING AND ADDITIONAL BIOLOGICAL EVALUATION OF RACEMIC DERIVATIVES

Abstract

Sodium (5RS)-Z-6-(substituted methylene)penem-3-carboxylates (3) are extremely potent inhibitors of bacterial β-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.