Cargando…

Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents

This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure–activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a goo...

Descripción completa

Detalles Bibliográficos
Autores principales: Russo, Francesco, Gising, Johan, Åkerbladh, Linda, Roos, Annette K, Naworyta, Agata, Mowbray, Sherry L, Sokolowski, Anders, Henderson, Ian, Alling, Torey, Bailey, Mai A, Files, Megan, Parish, Tanya, Karlén, Anders, Larhed, Mats
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522185/
https://www.ncbi.nlm.nih.gov/pubmed/26246997
http://dx.doi.org/10.1002/open.201500001
_version_ 1782383931379679232
author Russo, Francesco
Gising, Johan
Åkerbladh, Linda
Roos, Annette K
Naworyta, Agata
Mowbray, Sherry L
Sokolowski, Anders
Henderson, Ian
Alling, Torey
Bailey, Mai A
Files, Megan
Parish, Tanya
Karlén, Anders
Larhed, Mats
author_facet Russo, Francesco
Gising, Johan
Åkerbladh, Linda
Roos, Annette K
Naworyta, Agata
Mowbray, Sherry L
Sokolowski, Anders
Henderson, Ian
Alling, Torey
Bailey, Mai A
Files, Megan
Parish, Tanya
Karlén, Anders
Larhed, Mats
author_sort Russo, Francesco
collection PubMed
description This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure–activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.
format Online
Article
Text
id pubmed-4522185
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher John Wiley & Sons, Ltd
record_format MEDLINE/PubMed
spelling pubmed-45221852015-08-05 Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents Russo, Francesco Gising, Johan Åkerbladh, Linda Roos, Annette K Naworyta, Agata Mowbray, Sherry L Sokolowski, Anders Henderson, Ian Alling, Torey Bailey, Mai A Files, Megan Parish, Tanya Karlén, Anders Larhed, Mats ChemistryOpen Full Papers This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure–activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs. John Wiley & Sons, Ltd 2015-06 2015-04-17 /pmc/articles/PMC4522185/ /pubmed/26246997 http://dx.doi.org/10.1002/open.201500001 Text en © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Full Papers
Russo, Francesco
Gising, Johan
Åkerbladh, Linda
Roos, Annette K
Naworyta, Agata
Mowbray, Sherry L
Sokolowski, Anders
Henderson, Ian
Alling, Torey
Bailey, Mai A
Files, Megan
Parish, Tanya
Karlén, Anders
Larhed, Mats
Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
title Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
title_full Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
title_fullStr Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
title_full_unstemmed Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
title_short Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
title_sort optimization and evaluation of 5-styryl-oxathiazol-2-one mycobacterium tuberculosis proteasome inhibitors as potential antitubercular agents
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522185/
https://www.ncbi.nlm.nih.gov/pubmed/26246997
http://dx.doi.org/10.1002/open.201500001
work_keys_str_mv AT russofrancesco optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT gisingjohan optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT akerbladhlinda optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT roosannettek optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT naworytaagata optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT mowbraysherryl optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT sokolowskianders optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT hendersonian optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT allingtorey optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT baileymaia optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT filesmegan optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT parishtanya optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT karlenanders optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents
AT larhedmats optimizationandevaluationof5styryloxathiazol2onemycobacteriumtuberculosisproteasomeinhibitorsaspotentialantitubercularagents