Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity
Résumé
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
Origine : Fichiers produits par l'(les) auteur(s)
Licence : Domaine public
Licence : Domaine public