title: 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.
authors.affiliation: Université Lille Nord de France, F-59000 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: Baptiste
authors.initials: B
authors.lastname: Villemagne
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blondiaux
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
authors.forename: Catherine
authors.initials: C
authors.lastname: Piveteau
authors.forename: Vanessa
authors.initials: V
authors.lastname: Mathys
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Flament
authors.forename: Juergen
authors.initials: J
authors.lastname: Siepmann
authors.forename: Vincent
authors.initials: V
authors.lastname: Villeret
authors.forename: Alexandre
authors.initials: A
authors.lastname: Wohlkönig
authors.forename: René
authors.initials: R
authors.lastname: Wintjens
authors.forename: Sameh H
authors.initials: SH
authors.lastname: Soror
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: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004357:Drug Synergism; D005000:Ethionamide / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011355:Prodrugs / Q000493:pharmacokinetics*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C570905:5,5,5-trifluoro-1-(4-(3-thiazol-2-yl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)pentan-1-one; D000995:Antitubercular Agents; C481661:EthR protein, Mycobacterium tuberculosis; D010069:Oxadiazoles; D010880:Piperidines; D011355:Prodrugs; D012097:Repressor Proteins; D005000:Ethionamide