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

Dominc E. Spurling, Emily J. Baker, George Reggie Kingsley-Moore, Rifahath Mon Neyya Ppadath, Nachiket Deepak More, Nawaf Al-Maharik, James Harrison, Jonathan A.G. Cox, David O'Hagan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Article numbere202401050
Number of pages9
JournalEuropean Journal of Organic Chemistry
VolumeEarly View
Early online date9 Nov 2024
DOIs
Publication statusE-pub ahead of print - 9 Nov 2024

Keywords

  • Medicinal chemistry
  • B-lactams
  • Anti-mycobacterial
  • Mechanism based inhibition
  • Organofluorine chemistry

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