Aryl‐Fluorocyclopropane <i>β</i>‐Lactams with Activity Against <i>Mycobacteroides abscessus</i> and <i>Mycobacterium bovis BCG</i>

Abstract A novel series of aryl‐α‐fluorocyclopropyl 1 and α,β,β‐ trifluorocyclopropyl 2 β ‐lactams have been prepared and their activity explored across various Mycobacteria and also the ESKAPE panel of pathogens. The most active of these compounds 1 a displayed good activity against clinically challenging Mycobacteria such as M. bovis BCG (MIC 0.39 mg/mL)) and did not show any significant activity against the ESKAPE pathogens indicating selectivity for this otherwise challenging class of pathogen. Compound 1 a was however rapidly metabolised and toxic to a human model cell line (HepG2) limiting its clinical development at this stage. The compounds were designed to exploit a fluoride ion elimination mechanism concomitant with β ‐lactam ring opening, as the basis of a mechanism induced trigger to generate a reactive intermediate (suicide inhibition). In model alkoxide reactions a representative from both classes 1 and 2 resulted in β ‐lactam ring opening but only the more active mono‐fluoro cyclopropane series 1 triggered fluoride ion elimination after ring opening and this may form the basis of its activity.