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

David O'Hagan; Dominic E. Spurling; Emily J. Baker; George Kingsley-Moore; Rifahath Mon Neyya Ppadath; Nachiket D. More; Nawaf D. Al-Maharik; James Harrison; Jonathan A. G. Cox

doi:10.1002/ejoc.202401050

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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	European Journal of Organic Chemistry
Early online date	26 Sept 2024
DOIs	https://doi.org/10.1002/ejoc.202401050
Publication status	E-pub ahead of print - 26 Sept 2024

Bibliographical note

Copyright © 2024 Wiley-VCH GmbH. This is the peer reviewed version of the following article: 'David O'Hagan et al (2024). 'Aryl-fluorocyclopropane β-lactams with activity against Mycobacteroides abscessus and Mycobacterium bovis BCG,' European Journal of Organic Chemistry, e202401050', which has been published in final form at https://doi.org/10.1002/ejoc.202401050. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.

Keywords

anti-mycobacterial
b-lactams
mechanism based inhibition
medicinal chemistry
organofluorine chemistry

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O'Hagan, D., Spurling, D. E., Baker, E. J., Kingsley-Moore, G., Ppadath, R. M. N., More, N. D., Al-Maharik, N. D., Harrison, J., & Cox, J. A. G. (2024). Aryl‐fluorocyclopropane β‐lactams with activity against Mycobacteroides abscessus and Mycobacterium bovis BCG. European Journal of Organic Chemistry. Advance online publication. https://doi.org/10.1002/ejoc.202401050

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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.",

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AU - Kingsley-Moore, George

AU - Ppadath, Rifahath Mon Neyya

AU - More, Nachiket D.

AU - Al-Maharik, Nawaf D.

AU - Harrison, James

AU - Cox, Jonathan A. G.

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N2 - 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.

AB - 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.

KW - anti-mycobacterial

KW - b-lactams

KW - mechanism based inhibition

KW - medicinal chemistry

KW - organofluorine chemistry

UR - https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejoc.202401050

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DO - 10.1002/ejoc.202401050

M3 - Article

SN - 1434-193X

JO - European Journal of Organic Chemistry

JF - European Journal of Organic Chemistry

ER -

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

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Keywords

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