Intracellular and in vivo evaluation of ...
Document type :
Compte-rendu et recension critique d'ouvrage
PMID :
Title :
Intracellular and in vivo evaluation of imidazo [2,1-b]thiazole-5-carboxamide anti- tuberculosis compounds
Author(s) :
Moraski, Garrett [Auteur]
Deboosère, Nathalie [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Marshall, Kate [Auteur]
Weaver, Heath [Auteur]
Vandeputte, Alexandre [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Hastings, Courtney [Auteur]
Woolhiser, Lisa [Auteur]
Lenaerts, Anne [Auteur]
Brodin, Priscille [Auteur correspondant]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Miller, Marvin [Auteur correspondant]
Deboosère, Nathalie [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Marshall, Kate [Auteur]
Weaver, Heath [Auteur]
Vandeputte, Alexandre [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Hastings, Courtney [Auteur]
Woolhiser, Lisa [Auteur]
Lenaerts, Anne [Auteur]
Brodin, Priscille [Auteur correspondant]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Miller, Marvin [Auteur correspondant]
Journal title :
PLoS One
Pages :
e0227224
Publisher :
Public Library of Science
Publication date :
2020-01-06
ISSN :
1932-6203
HAL domain(s) :
Sciences du Vivant [q-bio]/Sciences pharmaceutiques/Pharmacologie
Sciences du Vivant [q-bio]/Médecine humaine et pathologie/Maladies infectieuses
Sciences du Vivant [q-bio]/Médecine humaine et pathologie/Maladies infectieuses
English abstract : [en]
The imidazo[2,1-b]thiazole-5-carboxamides (ITAs) are a promising class of anti-tuberculosis agents shown to have potent activity in vitro and to target QcrB, a key component of the mycobacterial cytochrome bcc-aa3 super ...
Show more >The imidazo[2,1-b]thiazole-5-carboxamides (ITAs) are a promising class of anti-tuberculosis agents shown to have potent activity in vitro and to target QcrB, a key component of the mycobacterial cytochrome bcc-aa3 super complex critical for the electron transport chain. Herein we report the intracellular macrophage potency of nine diverse ITA analogs with MIC values ranging from 0.0625-2.5 μM and mono-drug resistant potency ranging from 0.0017 to 7 μM. The in vitro ADME properties (protein binding, CaCo-2, human microsomal stability and CYP450 inhibition) were determined for an outstanding compound of the series, ND-11543. ND-11543 was tolerable at >500 mg/kg in mice and at a dose of 200 mg/kg displayed good drug exposure in mice with an AUC(0-24h) >11,700 ng·hr/mL and a >24 hr half-life. Consistent with the phenotype observed with other QcrB inhibitors, compound ND-11543 showed efficacy in a chronic murine TB infection model when dosed at 200 mg/kg for 4 weeks. The efficacy was not dependent upon exposure, as pre-treatment with a known CYP450-inhibitor did not substantially improve efficacy. The ITAs are an interesting scaffold for the development of new anti-TB drugs especially in combination therapy based on their favorable properties and novel mechanism of action.Show less >
Show more >The imidazo[2,1-b]thiazole-5-carboxamides (ITAs) are a promising class of anti-tuberculosis agents shown to have potent activity in vitro and to target QcrB, a key component of the mycobacterial cytochrome bcc-aa3 super complex critical for the electron transport chain. Herein we report the intracellular macrophage potency of nine diverse ITA analogs with MIC values ranging from 0.0625-2.5 μM and mono-drug resistant potency ranging from 0.0017 to 7 μM. The in vitro ADME properties (protein binding, CaCo-2, human microsomal stability and CYP450 inhibition) were determined for an outstanding compound of the series, ND-11543. ND-11543 was tolerable at >500 mg/kg in mice and at a dose of 200 mg/kg displayed good drug exposure in mice with an AUC(0-24h) >11,700 ng·hr/mL and a >24 hr half-life. Consistent with the phenotype observed with other QcrB inhibitors, compound ND-11543 showed efficacy in a chronic murine TB infection model when dosed at 200 mg/kg for 4 weeks. The efficacy was not dependent upon exposure, as pre-treatment with a known CYP450-inhibitor did not substantially improve efficacy. The ITAs are an interesting scaffold for the development of new anti-TB drugs especially in combination therapy based on their favorable properties and novel mechanism of action.Show less >
Language :
Anglais
Popular science :
Non
ANR Project :
Une galénique " verte " à base de nanoparticules de cyclodextrines pour un traitement plus efficace de la tuberculose
Naissance d'un tueur: facteurs génétiques et adaptations métaboliques impliquées dans l'émergence des bacilles tuberculeux épidémiques
Plateau de microscopie de criblage à haut débit et d'analyse à très haute résolution
Naissance d'un tueur: facteurs génétiques et adaptations métaboliques impliquées dans l'émergence des bacilles tuberculeux épidémiques
Plateau de microscopie de criblage à haut débit et d'analyse à très haute résolution
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