5 research outputs found
Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell <i>Mycobacterium tuberculosis</i> Assays
Small-molecule inhibitors
of the mycobacterial transcriptional
repressor EthR have previously been shown to act as boosters of the
second-line antituberculosis drug ethionamide. Fragment-based
drug discovery approaches have been used in the past to make highly
potent EthR inhibitors with ethionamide boosting activity both <i>in vitro</i> and <i>ex vivo</i>. Herein, we report
the development of fragment-sized EthR ligands with nanomolar minimum
effective concentration values for boosting the ethionamide
activity in <i>Mycobacterium tuberculosis</i> whole-cell
assays
Ethionamide Boosters. 2. Combining Bioisosteric Replacement and Structure-Based Drug Design To Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors
Mycobacterial transcriptional repressor EthR controls
the expression
of EthA, the bacterial monooxygenase activating ethionamide, and is
thus largely responsible for the low sensitivity of the human pathogen <i>Mycobacterium tuberculosis</i> to this antibiotic. We recently
reported structure–activity relationships of a series of 1,2,4-oxadiazole
EthR inhibitors leading to the discovery of potent ethionamide boosters.
Despite high metabolic stability, pharmacokinetic evaluation revealed
poor mice exposure; therefore, a second phase of optimization was
required. Herein a structure–property relationship study is
reported according to the replacement of the two aromatic heterocycles:
2-thienyl and 1,2,4-oxadiazolyl moieties. This work was done using
a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR
and on the human pathogen <i>Mycobacterium tuberculosis</i>. Thanks to this process, we identified compound <b>42</b> (BDM41906), which displays improved efficacy in addition to high
exposure to mice after oral administration