Cyclobutanone analogues of beta‐lactam antibiotics: beta‐lactamase inhibitors with untapped potential?

Abstract

Beta‐Lactam antibiotics have been used for many years to treat bacterial infections. However the effective treatment of an increasing range of microbial infections is threatened by bacterial resistance to beta‐lactams: the prolonged, widespread and at times reckless use of these drugs has spawned widespread resistance, which renders them ineffective against many bacterial strains. The cyclobutanone ring system is isosteric with beta‐lactam: in cyclobutanone analogues, the eponymous cyclic amide is replaced with an all‐carbon ring, the amide N substituted by a tertiary C–H α to a ketone. Cyclobutanone analogues of various beta‐lactam antibiotics have been investigated over the last thirty‐five years, initially as prospective antibiotics in their own right and inhibitors of the beta‐lactamase enzymes that impart resistance to beta‐lactams, more recently as inhibitors of other serine proteases and mechanistic probes of beta‐lactam biosynthesis. Cyclobutanone analogues of the penam ring system are the first reversible inhibitors to demonstrate moderate activity against all classes of beta‐lactamase, while other compounds from this family inhibit Streptomyces R61 DD‐carboxypeptidase/transpeptidase, human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE). But has their potential as enzyme inhibitors been fully exploited? Challenges in synthesising diversely functionalised derivatives mean only a limited number and structural diversity of cyclobutanone beta‐lactam analogues have been made and evaluated to date. This review surveys the different synthetic approaches that have been taken to these compounds, investigations to evaluate their biological activity, and prospects for future developments in this area.