Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity - CNRS - Centre national de la recherche scientifique Access content directly
Journal Articles ACS Infectious Diseases Year : 2020

Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity

Alexandre Wohlkönig
  • Function : Author
René Wintjens
  • Function : Author
Xue Li
Ruxandra Gref
Priscille Brodin

Abstract

Killing more than one million people each year, tuberculosis remains the leading cause of death from a single infectious agent. The growing threat of multidrug resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. EthR, a mycobacterial transcriptional regulator, is involved in the control of the bioactivation of the second-line drug ethionamide. We have previously reported the discovery of in vitro nanomolar boosters of ethionamide through fragment-based approaches. In this study, we have further explored the structure-activity and structure-property relationships in this chemical family. By combining structure-based drug-design and in vitro evaluation of the compounds, we identified compound 27 (BDM71339), the first fragment-based ethionamide booster which proved active in vivo, in an acute model of tuberculosis infection.
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Dates and versions

hal-03096012 , version 1 (05-02-2024)

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Baptiste Villemagne, Arnaud Machelart, Ngoc Chau Tran, Marion Flipo, Martin Moune, et al.. Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity. ACS Infectious Diseases, 2020, 6 (3), pp.366-378. ⟨10.1021/acsinfecdis.9b00277⟩. ⟨hal-03096012⟩
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