Novel imidazole substituted 6-methylidene-penems as broad-spectrum β-lactamase inhibitors

A series of novel imidazole substituted 6-methylidene-penems has been synthesized (R = heterocycle) and was shown to be potent, broad-spectrum β-lactamase inhibitors against class-A and class-C enzymes. The present paper deals with the design, synthesis, and structure-activity relationships (SAR) of compounds 11-15. β-Lactamases are serine and metallo-dependent enzymes produced by the bacteria in defense against β-lactam antibiotics. Production of class-A, class-B, and class-C enzymes by the bacteria make the use of β-lactam antibiotics ineffective in certain cases. To overcome resistance to β-lactam antibiotics, several β-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam are widely used in the clinic in combination with β-lactam antibiotics. However, single point mutations within these enzymes have allowed bacteria to overcome the inhibitory effect of the commercially approved β-lactamase inhibitors. Although the commercially available β-lactamase inhibitor/β-lactam antibiotic combinations are effective against class-A producing bacteria and many extended spectrum β-lactamase (ESBL's) producing bacteria they are less effective against class-C enzymes expressing bacteria. To circumvent this problem, based on modeling studies several novel imidazole substituted 6-methylidene-penem derivatives were synthesized and tested against various β-lactamase producing isolates. The present paper deals with the synthesis and structure-activity relationships (SAR) of these compounds.