Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.ejmech.2022.114404 http://hdl.handle.net/11449/241827 |
Resumo: | An exploration of the chemical space around a 2,5-dimethylpyrrole scaffold of antitubercular hit compound 1 has led to the identification of new derivatives active against Mycobacterium tuberculosis and multidrug-resistant clinical isolates. Analogues incorporating a cyclohexanemethyl group on the methyleneamine side chain at C3 of the pyrrole core, including 5n and 5q, exhibited potent inhibitory effects against the M. tuberculosis strains, substantiating the essentiality of the moiety to their antimycobacterial activity. In addition, selected derivatives showed promising cytotoxicity profiles against human pulmonary fibroblasts and/or murine macrophages, proved to be effective in inhibiting the growth of intracellular mycobacteria, and elicited either bactericidal effects, or bacteriostatic activity comparable to 1. Computational studies revealed that the new compounds bind to the putative target, MmpL3, in a manner similar to that of known inhibitors BM212 and SQ109. |
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Repositório Institucional da UNESP |
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Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogationAntimicrobial resistanceAntimycobacterialMDR-TBPyrroleSARTuberculosisAn exploration of the chemical space around a 2,5-dimethylpyrrole scaffold of antitubercular hit compound 1 has led to the identification of new derivatives active against Mycobacterium tuberculosis and multidrug-resistant clinical isolates. Analogues incorporating a cyclohexanemethyl group on the methyleneamine side chain at C3 of the pyrrole core, including 5n and 5q, exhibited potent inhibitory effects against the M. tuberculosis strains, substantiating the essentiality of the moiety to their antimycobacterial activity. In addition, selected derivatives showed promising cytotoxicity profiles against human pulmonary fibroblasts and/or murine macrophages, proved to be effective in inhibiting the growth of intracellular mycobacteria, and elicited either bactericidal effects, or bacteriostatic activity comparable to 1. Computational studies revealed that the new compounds bind to the putative target, MmpL3, in a manner similar to that of known inhibitors BM212 and SQ109.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)School of Cancer and Pharmaceutical Sciences King's College London, 150 Stamford StreetTuberculosis Research Laboratory School of Pharmaceutical Sciences Sao Paulo State University (UNESP), Rod. Araraquara-Jau, km1Dipartimento di Biotecnologie Chimica e Farmacia Dipartimento di Eccellenza 2018-2022 University of Siena, via A. Moro 2Tuberculosis Research Laboratory School of Pharmaceutical Sciences Sao Paulo State University (UNESP), Rod. Araraquara-Jau, km1FAPESP: 2020/13497-4King's College LondonUniversidade Estadual Paulista (UNESP)University of SienaSemenya, DorothyTouitou, MeirMasci, DomizianaRibeiro, Camila Maringolo [UNESP]Pavan, Fernando Rogerio [UNESP]Dos Santos Fernandes, Guilherme FelipeGianibbi, BeatriceManetti, FabrizioCastagnolo, Daniele2023-03-02T00:29:32Z2023-03-02T00:29:32Z2022-07-05info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.ejmech.2022.114404European Journal of Medicinal Chemistry, v. 237.1768-32540223-5234http://hdl.handle.net/11449/24182710.1016/j.ejmech.2022.1144042-s2.0-85129861578Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengEuropean Journal of Medicinal Chemistryinfo:eu-repo/semantics/openAccess2024-06-24T13:08:36Zoai:repositorio.unesp.br:11449/241827Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-06T00:12:21.054587Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation |
title |
Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation |
spellingShingle |
Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation Semenya, Dorothy Antimicrobial resistance Antimycobacterial MDR-TB Pyrrole SAR Tuberculosis |
title_short |
Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation |
title_full |
Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation |
title_fullStr |
Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation |
title_full_unstemmed |
Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation |
title_sort |
Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation |
author |
Semenya, Dorothy |
author_facet |
Semenya, Dorothy Touitou, Meir Masci, Domiziana Ribeiro, Camila Maringolo [UNESP] Pavan, Fernando Rogerio [UNESP] Dos Santos Fernandes, Guilherme Felipe Gianibbi, Beatrice Manetti, Fabrizio Castagnolo, Daniele |
author_role |
author |
author2 |
Touitou, Meir Masci, Domiziana Ribeiro, Camila Maringolo [UNESP] Pavan, Fernando Rogerio [UNESP] Dos Santos Fernandes, Guilherme Felipe Gianibbi, Beatrice Manetti, Fabrizio Castagnolo, Daniele |
author2_role |
author author author author author author author author |
dc.contributor.none.fl_str_mv |
King's College London Universidade Estadual Paulista (UNESP) University of Siena |
dc.contributor.author.fl_str_mv |
Semenya, Dorothy Touitou, Meir Masci, Domiziana Ribeiro, Camila Maringolo [UNESP] Pavan, Fernando Rogerio [UNESP] Dos Santos Fernandes, Guilherme Felipe Gianibbi, Beatrice Manetti, Fabrizio Castagnolo, Daniele |
dc.subject.por.fl_str_mv |
Antimicrobial resistance Antimycobacterial MDR-TB Pyrrole SAR Tuberculosis |
topic |
Antimicrobial resistance Antimycobacterial MDR-TB Pyrrole SAR Tuberculosis |
description |
An exploration of the chemical space around a 2,5-dimethylpyrrole scaffold of antitubercular hit compound 1 has led to the identification of new derivatives active against Mycobacterium tuberculosis and multidrug-resistant clinical isolates. Analogues incorporating a cyclohexanemethyl group on the methyleneamine side chain at C3 of the pyrrole core, including 5n and 5q, exhibited potent inhibitory effects against the M. tuberculosis strains, substantiating the essentiality of the moiety to their antimycobacterial activity. In addition, selected derivatives showed promising cytotoxicity profiles against human pulmonary fibroblasts and/or murine macrophages, proved to be effective in inhibiting the growth of intracellular mycobacteria, and elicited either bactericidal effects, or bacteriostatic activity comparable to 1. Computational studies revealed that the new compounds bind to the putative target, MmpL3, in a manner similar to that of known inhibitors BM212 and SQ109. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-07-05 2023-03-02T00:29:32Z 2023-03-02T00:29:32Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.ejmech.2022.114404 European Journal of Medicinal Chemistry, v. 237. 1768-3254 0223-5234 http://hdl.handle.net/11449/241827 10.1016/j.ejmech.2022.114404 2-s2.0-85129861578 |
url |
http://dx.doi.org/10.1016/j.ejmech.2022.114404 http://hdl.handle.net/11449/241827 |
identifier_str_mv |
European Journal of Medicinal Chemistry, v. 237. 1768-3254 0223-5234 10.1016/j.ejmech.2022.114404 2-s2.0-85129861578 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
European Journal of Medicinal Chemistry |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808129595354906624 |