�-lactamases are the primary cause of resistance to �-lactam antibiotics. This resistance can be overcome by co-administering the antibiotic with a �-lactamase inhibitor. However, continuous evolution of this resistance mechanism reinforces an urgent and serious need to improve �-lactamase inhibitors and maintain the clinical utility of �-lactam antibiotics. Boronic acids inhibitors of �-lactamases have been reported where the boron acts as a serine trap, inactivating the �-lactamase hydrolytic activity. Since boronic acids are often associated with poor drug-like properties, we report here a new class of boron-based �-lactamase inhibitor, benzoxaboroles, where the boron atom is incorporated into a fused aromatic ring system, which typically improves drug-like properties.Screening our chemical library of boron-containing compounds, we identified benzoxaboroles with promising and selective inhibitory activity against a panel of �-lactamase enzymes.  In this disclosure, we describe our research effort leading to benzoxaboroles that inhibit both class A and C �-lactamases with Ki values in low nanomolar range. We also present in vivo data on selected compounds that restore antibacterial activity of cefepime against Enterobacteriaceae expressing �-lactamase enzymes.

Novel benzoxaboroles as a new class of ß-lactamase inhibitors

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.