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

Abstract : 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.
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Submitted on : Monday, February 10, 2020 - 11:05:27 AM
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Garrett Moraski, Nathalie Deboosère, Kate Marshall, Heath Weaver, Alexandre Vandeputte, et al.. Intracellular and in vivo evaluation of imidazo [2,1-b]thiazole-5-carboxamide anti- tuberculosis compounds. PLoS ONE, Public Library of Science, 2020, 15 (1), pp.e0227224. ⟨10.1371/journal.pone.0227224⟩. ⟨inserm-02472354⟩

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