Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds

English version

Autoři: Garrett C. Moraski ^aff001; Nathalie Deboosère ^aff002; Kate L. Marshall ^aff001; Heath A. Weaver ^aff001; Alexandre Vandeputte ^aff002; Courtney Hastings ^aff003; Lisa Woolhiser ^aff003; Anne J. Lenaerts ^aff003; Priscille Brodin ^aff002; Marvin J. Miller ^aff004
Působiště autorů: Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana, United States of America ^aff001; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 –UMR 8204 –CIIL–Center for Infection and Immunity of Lille, Lille, France ^aff002; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America ^aff003; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America ^aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0227224

Souhrn

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.

Klíčová slova:

Animal models of infection – Blood plasma – High performance liquid chromatography – Macrophages – Mouse models – Mycobacterium tuberculosis – Spleen – Tuberculosis

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Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds

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