With the growing global problem of antibiotic resistance, the search for new potential treatment options has been the focus of many research groups. One strategy to overcome this problem is to develop compounds that will inhibit the β-lactamase enzymes, which hydrolyze β-lactam antibiotics. By targeting these enzymes, the traditional β-lactam antibiotics will be able to function as normal. From many years of research, some compounds have shown promising inhibition towards β-lactamase and have even become commercially available. The β-lactamase inhibitor is paired with the traditional β-lactam antibiotic. This prevents hydrolysis of the β-lactam and allows it to attack the bacteria. Unfortunately, there are only a handful of clinically-used inhibitors of β-lactamases, and resistance to them has developed. Compounds containing an aza-β-lactam ring are hypothesized to be potential inhibitors of β-lactamases. In contrast to the β-lactam, an aza-β-lactam contains a second nitrogen atom in the lactam ring. Upon nucleophilic attack by the β-lactamase, the resulting acyl-enzyme intermediate (a carbamate) is expected to be more hydrolytically stable than the corresponding acyl-enzyme intermediate of a β-lactam (an ester) due to the increased resonance stabilization afforded by the nitrogen. Several strategies have been explored to synthesize a library of compounds that contain the aza-β-lactam ring, to then be tested for β-lactamase inhibitory activity. These approaches include both traditional batch chemistry and of flow chemistry.

Strategies for synthesis of various aza-β-lactam derivatives as potential β-lactamase inhibitors

256th National Meeting (2018)

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