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Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides

A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxide...

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Autores principales: Thompson, Andrew M., Marshall, Andrew J., Maes, Louis, Yarlett, Nigel, Bacchi, Cyrus J., Gaukel, Eric, Wring, Stephen A., Launay, Delphine, Braillard, Stephanie, Chatelain, Eric, Mowbray, Charles E., Denny, William A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840523/
https://www.ncbi.nlm.nih.gov/pubmed/29191556
http://dx.doi.org/10.1016/j.bmcl.2017.10.067
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author Thompson, Andrew M.
Marshall, Andrew J.
Maes, Louis
Yarlett, Nigel
Bacchi, Cyrus J.
Gaukel, Eric
Wring, Stephen A.
Launay, Delphine
Braillard, Stephanie
Chatelain, Eric
Mowbray, Charles E.
Denny, William A.
author_facet Thompson, Andrew M.
Marshall, Andrew J.
Maes, Louis
Yarlett, Nigel
Bacchi, Cyrus J.
Gaukel, Eric
Wring, Stephen A.
Launay, Delphine
Braillard, Stephanie
Chatelain, Eric
Mowbray, Charles E.
Denny, William A.
author_sort Thompson, Andrew M.
collection PubMed
description A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.
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spelling pubmed-58405232018-03-08 Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides Thompson, Andrew M. Marshall, Andrew J. Maes, Louis Yarlett, Nigel Bacchi, Cyrus J. Gaukel, Eric Wring, Stephen A. Launay, Delphine Braillard, Stephanie Chatelain, Eric Mowbray, Charles E. Denny, William A. Bioorg Med Chem Lett Article A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies. Elsevier Science Ltd 2018-01-15 /pmc/articles/PMC5840523/ /pubmed/29191556 http://dx.doi.org/10.1016/j.bmcl.2017.10.067 Text en © 2017 The Authors. Published by Elsevier Ltd. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Thompson, Andrew M.
Marshall, Andrew J.
Maes, Louis
Yarlett, Nigel
Bacchi, Cyrus J.
Gaukel, Eric
Wring, Stephen A.
Launay, Delphine
Braillard, Stephanie
Chatelain, Eric
Mowbray, Charles E.
Denny, William A.
Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides
title Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides
title_full Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides
title_fullStr Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides
title_full_unstemmed Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides
title_short Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides
title_sort assessment of a pretomanid analogue library for african trypanosomiasis: hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5h-imidazo[2,1-b][1,3]thiazine 8-oxides
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840523/
https://www.ncbi.nlm.nih.gov/pubmed/29191556
http://dx.doi.org/10.1016/j.bmcl.2017.10.067
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