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

Baptiste Villemagne (1, 2) , Arnaud Machelart (1, 2) , Ngoc Chau Tran (1, 2) , Marion Flipo (1, 2) , Martin Moune (1) , Florence Leroux (1, 2) , Catherine Piveteau (1, 2) , Alexandre Wohlkönig , René Wintjens , Xue Li (3) , Ruxandra Gref (3) , Priscille Brodin (1) , Benoit Deprez (1, 2) , Alain Baulard (1) , Nicolas Willand (1, 2)

1 Institut Pasteur de Lille
2 M2SV - Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177
3 ISMO - Institut des Sciences Moléculaires d'Orsay

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.

Domaines: Chimie

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⟩