Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity

Autor: Alexandre Wohlkonig, Florence Leroux, Nicolas Willand, Ngoc Chau Tran, Xue Li, Arnaud Machelart, Marion Flipo, Catherine Piveteau, Ruxandra Gref, René Wintjens, Martin Moune, Priscille Brodin, Baptiste Villemagne, Benoit Deprez, Alain R. Baulard
Přispěvatelé: Department of Bio-engineering Sciences, Structural Biology Brussels, Institut des Sciences Moléculaires d'Orsay (ISMO), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Drug
Ethionamide booster
in vivo POC
Tuberculosis
mice
media_common.quotation_subject
030106 microbiology
Pharmacology
Biology
Crystallography
X-Ray
Mycobacterium tuberculosis
03 medical and health sciences
In vivo
Drug Discovery
medicine
[CHIM]Chemical Sciences
Animals
Ethionamide/chemistry
ComputingMilieux_MISCELLANEOUS
media_common
Tuberculosis/drug therapy
Mice
Inbred BALB C
Mycobacterium tuberculosis/drug effects
Oxadiazoles/chemistry
Sciences bio-médicales et agricoles
biology.organism_classification
medicine.disease
Structure-activity relationship
In vitro
3. Good health
030104 developmental biology
Infectious Diseases
Repressor Proteins/antagonists & inhibitors
Antitubercular Agents/chemistry
Drug Design
Ethionamide
Female
Fragment-based drug design
Infectious agent
medicine.drug
Zdroj: ACS Infectious Diseases
ACS Infectious Diseases, American Chemical Society, 2020, 6 (3), pp.366-378. ⟨10.1021/acsinfecdis.9b00277⟩
ACS infectious diseases, 6 (3
ISSN: 2373-8227
DOI: 10.1021/acsinfecdis.9b00277⟩
Popis: Killing more than one million people each year, tuberculosis remains the leading cause of death from a single infectious agent. The growing threat of multidrug-resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. EthR, a mycobacterial transcriptional regulator, is involved in the control of the bioactivation of the second-line drug ethionamide. We have previously reported the discovery of in vitro nanomolar boosters of ethionamide through fragment-based approaches. In this study, we have further explored the structure-activity and structure-property relationships in this chemical family. By combining structure-based drug design and in vitro evaluation of the compounds, we identified a new oxadiazole compound as the first fragment-based ethionamide booster which proved to be active in vivo, in an acute model of tuberculosis infection.
info:eu-repo/semantics/published
Databáze: OpenAIRE
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