5 research outputs found
Fragment-Sized EthR Inhibitors Exhibit Exceptionally Strong Ethionamide Boosting Effect in Whole-Cell <i>Mycobacterium tuberculosis</i> Assays
No full textSmall-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
No full textMycobacterial 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
