Novel sulfer containing monocyclic beta-lactams as serine enzyme inhibitors

Drug resistance has become a global problem in virtually all areas of infectious diseases. The urgent need for developing new drugs and identifying new targets is a major focus of the pharmaceutical research. Serine proteases are widely present in the nature from prokaryotic bacteria through fungi and viruses to eukaryotic mammalian proteases. Development of novel f3lactam inhibitors of enzymes, which have active site serine, such as beta-lactamases and human leukocyte elastase, is the purpose of this research. The intention behind the design of these enzyme inhibitors is to broaden the activity of current beta-lactamase inhibitors by combining a suicide inhibitor feature. The beta-lactam ring carries an attachment poisonous to the bacteria that would be released only upon exposure of the compound to the beta-lactamase produced by the bacteria. The presence of protected and free thiols as part of the beta-lactam structure contributes to additional inhibitory properties. Structure-activity relationship is used to create library of desired drug candidates. The synthesis, purification and characterization of several new monocyclic beta-lactams are reported. Several of the products demonstrated significant intrinsic antimicrobial activity against clinical isolates of beta-lactamase producing bacteria, Moraxella caltharalis. The results of this study allowed us to further expand the structure-activity relationship data for this class of compounds and create agents with potential clinical application.