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

Abstract

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 Mycobacterium tuberculosis 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 Mycobacterium tuberculosis. Thanks to this process, we identified compound 42 (BDM41906), which displays improved efficacy in addition to high exposure to mice after oral administration.

An ethA-ethR -Deficient Mycobacterium bovis BCG Mutant Displays Increased Adherence to Mammalian Cells and Greater Persistence In Vivo , Which Correlate with Altered Mycolic Acid Composition

“…EthR-HexOc complexes were shown to prevent the binding of EthR to its target promoter region, thereby leading to derepression of ethA-ethR transcription and suggesting that regulation of the ethA-ethR locus is more complex than initially thought. More recently, the identification of small synthetic inhibitors of EthR that boost the anti-TB activity of ETH in vivo was reported, which may prompt reconsideration of ETH as a possible first-line anti-TB drug (27)(28)(29).…”

Antimycobacterial drugs currently in Phase II clinical trials and preclinical phase for tuberculosis treatment

“…Based on a combination of structure-based drug design and in vitro/ ex vivo evaluations of ETH boosters on the targeted protein EthR and on the human pathogen M. tuberculosis, a second phase optimization of the compound BDM31343 led to the replacement of the two aromatic heterocycles: 2-thienyl and 1,2,4-oxadiazolyl moieties. That process allowed identification of BDM41906, which displays improved efficacy in addition to high exposure to mice after oral administration [60]. This latest development indicates that EthR inhibitors could be used to boost ETH antimycobacterial activity.…”

Every Jack has His Jill: Finding a Target for Your Combinatorial Library

“…The downside of this approach is that we are not able to present experimental data for our prospective library proposals (the starting library or the derivatives for the targets we hit). As a starting point we chose a publication from the Journal of Medicinal Chemistry from 2012 which describes structurebased drug design for a series of potent 1,2,4-oxadiazoles, which target M. tuberculosis transcriptional repressor EthR (see Figure 3a for examples) [33]. We designed a combinatorial library, that is similar but distinct to the published compounds from ChEMBL, with the aim to demonstrate that the developed methodology is able (i) to recover the compounds from the publication and to show that EthR protein can be identified among the top targets, (ii) to identify potential new targets for our example library, (iii) to provide examples of target-fishing-based library modifications and (iv) to provide examples of the short-comings of such a fully automatic approach and to highlight the importance of expert interaction.…”

“…3O8H: Alternate binding mode: Our library was intentionally designed to be chemically similar to the EthR inhibitor BDM41906 [33] (PDB ID: 3SFI). 3G1M and 3SFI have the same overall shape, the library compounds dock consistently into both pockets (results are not shown).…”