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

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 a new oxadiazole compound as the first fragment-based ethionamide booster which proved to be active in vivo, in an acute model of tuberculosis infection.

Application of an immobilised amylose-based chiral stationary phase to the development of new monoamine oxidase B inhibitors.

A direct HPLC enantioseparation of three new chiral oxadiazoline derivatives endowed with potential MAO-B inhibitory activity was accomplished on the immobilised Chiralpak IA chiral stationary phase. Multi-mg amounts of enantiomers with high enantiomeric purity (ee> or =98%) were rapidly collected using pure dichloromethane as eluent. The absolute configuration and chiroptical properties of the enantiomers isolated at semipreparative scale were exhaustively determined.