title: Ethionamide boosters: synthesis, biological activity, and structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors.
abstract: We report in this article an extensive structure-activity relationships (SAR) study with 58 thiophen-2-yl-1,2,4-oxadiazoles as inhibitors of EthR, a transcriptional regulator controling ethionamide bioactivation in Mycobacterium tuberculosis. We explored the replacement of two key fragments of the starting lead BDM31343. We investigated the potency of all analogues to boost subactive doses of ethionamide on a phenotypic assay involving M. tuberculosis infected macrophages and then ascertained the mode of action of the most active compounds using a functional target-based surface plasmon resonance assay. This process revealed that introduction of 4,4,4-trifluorobutyryl chain instead of cyanoacetyl group was crucial for intracellular activity. Replacement of 1,4-piperidyl by (R)-1,3-pyrrolidyl scaffold did not enhance activity but led to improved pharmacokinetic properties. Furthermore, the crystal structures of ligand-EthR complexes were consistent with the observed SAR. In conclusion, we identified EthR inhibitors that boost antibacterial activity of ethionamide with nanomolar potency while improving solubility and metabolic stability.
authors.affiliation: Université Lille Nord de France, Lille, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Flipo
authors.forename: Matthieu
authors.initials: M
authors.lastname: Desroses
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lecat-Guillet
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dirié
authors.forename: Xavier
authors.initials: X
authors.lastname: Carette
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
authors.forename: Catherine
authors.initials: C
authors.lastname: Piveteau
authors.forename: Fatma
authors.initials: F
authors.lastname: Demirkaya
authors.forename: Zoé
authors.initials: Z
authors.lastname: Lens
authors.forename: Prakash
authors.initials: P
authors.lastname: Rucktooa
authors.forename: Vincent
authors.initials: V
authors.lastname: Villeret
authors.forename: Thierry
authors.initials: T
authors.lastname: Christophe
authors.forename: Hee Kyoung
authors.initials: HK
authors.lastname: Jeon
authors.forename: Camille
authors.initials: C
authors.lastname: Locht
authors.forename: Priscille
authors.initials: P
authors.lastname: Brodin
authors.forename: Benoit
authors.initials: B
authors.lastname: Déprez
authors.forename: Alain R
authors.initials: AR
authors.lastname: Baulard
authors.forename: Nicolas
authors.initials: N
authors.lastname: Willand
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D005000:Ethionamide / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D000995:Antitubercular Agents; D017931:DNA Primers; C481661:EthR protein, Mycobacterium tuberculosis; D010069:Oxadiazoles; D012097:Repressor Proteins; D005000:Ethionamide