Efficient analoging around ethionamide to explore thioamides bioactivation pathways triggered by boosters in Mycobacterium tuberculosis.

Autor: Prieri M; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France., Frita R; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France., Probst N; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France., Sournia-Saquet A; CNRS, LCC (Laboratoire de Chimie de Coordination UPR 8241), 205 route de Narbonne, F-31077 Toulouse, France; Univ. Toulouse, Université Paul Sabatier, F-31077 Toulouse, France., Bourotte M; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France., Déprez B; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France., Baulard AR; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France., Willand N; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France. Electronic address: nicolas.willand@univ-lille.fr.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2018 Nov 05; Vol. 159, pp. 35-46. Date of Electronic Publication: 2018 Sep 20.
DOI: 10.1016/j.ejmech.2018.09.038
Abstrakt: Ethionamide is a key antibiotic prodrug of the second-line chemotherapy regimen to treat tuberculosis. It targets the biosynthesis of mycolic acids thanks to a mycobacterial bioactivation carried out by the Baeyer-Villiger monooxygenase EthA, under the control of a transcriptional repressor called EthR. Recently, the drug-like molecule SMARt-420, which triggers a new transcriptional regulator called EthR2, allowed the derepression a cryptic alternative bioactivation pathway of ethionamide. In order to study the bioactivation of a collection of thioisonicotinamides through the two bioactivation pathways, we developed a new two-step chemical pathway that led to the efficient synthesis of eighteen ethionamide analogues. Measurements of the antimycobacterial activity of these derivatives, used alone and in combination with boosters BDM41906 or SMARt-420, suggest that the two different bioactivation pathways proceed via the same mechanism, which implies the formation of similar metabolites. In addition, an electrochemical study of the aliphatic thioisonicotinamide analogues was undertaken to see whether their oxidation potential correlates with their antitubercular activity measured in the presence or in the absence of the two boosters.
(Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: