Journal
PLOS ONE
Volume 15, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0227224
Keywords
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Categories
Funding
- National Institutes of Health [R37AI054193]
- National Institute of Allergy and Infectious Diseases [HHSN272201100009I]
- MJ Murdock Charitable Trust
- NIH [P20GM103474]
- NSF-Major Research Instrumentation program (NSF-MRI) [DBI1532078]
- Murdock Charitable Trust Foundation [015066:MNL]
- MSU Vice-President for Research and Economic Development office
- European Community (ERC-STG INTRACELLTB) [260901, 260872]
- Agence Nationale de la Recherche [ANR-10-EQPX-04-01, ANR-14-CE08-0017, ANR16-CE35-0009]
- Feder [12001407]
- Region Nord Pas de Calais [12000080]
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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 mu M and mono-drug resistant potency ranging from 0.0017 to 7 mu M. The in vitro ADME properties (protein binding, CaCo-2, human microsomal stability and CYP450 inhibition) were determined for an outstanding compound of the series, ND11543. 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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