Title :

A novel codrug made of the combination of ethionamide and its potentiating booster: synthesis, self-assembly into nanoparticles and antimycobacterial evaluation

Author(s) :

Pastor, Alexandra [Auteur]
Institut Galien Paris-Saclay [IGPS]
Machelart, Arnaud [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Li, Xue [Auteur]
Institut des Sciences Moléculaires d'Orsay [ISMO]
Willand, nicolas [Auteur]
Médicaments et molécules pour les systèmes vivants - U 1177 [M2SV]
Baulard, Alain [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Brodin, Priscille [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Gref, Ruxandra [Auteur]
Institut des Sciences Moléculaires d'Orsay [ISMO]
Desmaele, Didier [Auteur]
Institut Galien Paris-Saclay [IGPS]

Journal title :

Organic & biomolecular chemistry

Pages :

5129 - 5137

Publisher :

Royal Society of Chemistry

Publication date :

2019

ISSN :

1477-0520

HAL domain(s) :

Chimie/Chimie thérapeutique
Chimie/Chimie organique

English abstract : [en]

Ethionamide (ETH) is one of the most widely used second-line chemotherapeutic drugs for the treatment of multi-drug-resistant tuberculosis. The bioactivation and activity of ETH is dramatically potentiated by a family of ...
Show more >Ethionamide (ETH) is one of the most widely used second-line chemotherapeutic drugs for the treatment of multi-drug-resistant tuberculosis. The bioactivation and activity of ETH is dramatically potentiated by a family of molecules called "boosters" among which BDM43266 is one of the most potent. However, the co-administration of these active molecules is hampered by their low solubility in biological media and by the strong tendency of ETH to crystallize. A novel strategy that involves synthesizing a codrug able to self-associate into nanoparticles prone to be taken up by infected macrophages is proposed here. This codrug is designed by tethering N-hydroxymethyl derivatives of both ETH and its booster through a glutaric linker. This codrug self-assembles into nanoparticles of around 200 nm, stable upon extreme dilution without disaggregating as well as upon concentration. The nanoparticles of the codrug can be intranasally administered overcoming the unfavorable physico-chemical profiles of the parent drugs. Intrapulmonary delivery of the codrug nanoparticles to Mtb infected mice via the intranasal route at days 7, 9, 11, 14, 16 and 18 post-infection reduces the bacterial load in the lungs by a factor of 6.Show less >

Language :

Anglais

Popular science :

Non

ANR Project :

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Collections :

• Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017

Source :

Harvested from HAL