Work

Aryl‐Fluorocyclopropane β‐Lactams with Activity Against Mycobacteroides abscessus and Mycobacterium bovis BCG

Year: 2024

Type: article

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.

Source: European Journal of Organic Chemistry

DOI: 10.1002/ejoc.202401050