Aryl‐fluorocyclopropane β‐lactams with activity against Mycobacteroides abscessus and Mycobacterium bovis BCG

Abstract

A novel series of aryl-α-fluorocyclopropyl 1 and α,β,β-trifluorocyclopropyl 2β-lactams have been prepared and their activity explored across various Mycobacteria and also the ESKAPE panel of pathogens. The most active of these compounds 1a 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 1a 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.