Projects per year
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 language | English |
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Article number | e202401050 |
Number of pages | 9 |
Journal | European Journal of Organic Chemistry |
Volume | Early View |
Early online date | 9 Nov 2024 |
DOIs | |
Publication status | E-pub ahead of print - 9 Nov 2024 |
Keywords
- Medicinal chemistry
- B-lactams
- Anti-mycobacterial
- Mechanism based inhibition
- Organofluorine chemistry
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Dive into the research topics of 'Aryl-fluorocyclopropane β-lactams with activity against Mycobacteroides abscessus and Mycobacterium bovis BCG'. Together they form a unique fingerprint.Projects
- 2 Finished
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PhD Studentship Dominic Spurling: PhD studentship Dominic Spurling
O'Hagan, D. (PI)
1/09/20 → 30/04/24
Project: Standard
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Partially fluorinated alkyl motifs: Partially fluorinated alkyl motifs for pharmaceuticals and agrochemicals research
O'Hagan, D. (PI)
7/04/18 → 15/07/21
Project: Standard