Synthesis and antibacterial properties of 3-amino-β-lactams bearing a heteroatom-containing C4 substituent.

Abstract

The rise of antimicrobial resistance has spurred the search for innovative antibiotics, with monocyclic 3-amino-β-lactams - aztreonam standing out as key example - showing significant potential. In particular, C4-functionalized 3-amino-β-lactams have emerged as a promising subclass that can potentially improve the activity, stability and cellular permeability of the compounds. This review outlines various synthetic methodologies available for the construction of 3-amino-β-lactams bearing a heteroatom-containing substituent at C4, with the heteroatom connected to the ring system either directly or via a methylene bridge. Special attention is devoted to 3-amino-4-hydroxymethyl-β-lactams and 3-amino-4-acetoxy-β-lactams as versatile synthetic intermediates. Moreover, the effect of these C4 substituents on the biological activity of the corresponding 3-amino-β-lactams is discussed in detail. A better understanding of synthetic protocols and antibacterial properties related to this underexplored class of monocyclic 3-amino-β-lactams might contribute to address the current antibiotics problems we are facing more efficiently.