Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant Mycobacteria

Detalhes bibliográficos
Autor(a) principal: Semenya, Dorothy
Data de Publicação: 2022
Outros Autores: Touitou, Meir, Ribeiro, Camila Maringolo [UNESP], Pavan, Fernando Rogerio [UNESP], Pisano, Luca, Singh, Vinayak, Chibale, Kelly, Bano, Georg, Toscani, Anita, Manetti, Fabrizio, Gianibbi, Beatrice, Castagnolo, Daniele
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNESP
Texto Completo: http://dx.doi.org/10.1021/acsmedchemlett.1c00431
http://hdl.handle.net/11449/233891
Resumo: A series of indolyl-3-methyleneamines incorporating lipophilic side chains were designed through a structural rigidification approach and synthesized for investigation as new chemical entities against Mycobacterium tuberculosis (Mtb). The screening led to the identification of a 6-chloroindole analogue 7j bearing an N-octyl chain and a cycloheptyl moiety, which displayed potent in vitro activity against laboratory and clinical Mtb strains, including a pre-extensively drug-resistant (pre-XDR) isolate. 7j also demonstrated a marked ability to restrict the intracellular growth of Mtb in murine macrophages. Further assays geared toward mechanism of action elucidation have thus far ruled out the involvement of various known promiscuous targets, thereby suggesting that the new indole 7j may inhibit Mtb via a unique mechanism.
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spelling Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant MycobacteriaAntimicrobial resistanceIndoleMDR-TBPyrroleTuberculosisXDR-TBA series of indolyl-3-methyleneamines incorporating lipophilic side chains were designed through a structural rigidification approach and synthesized for investigation as new chemical entities against Mycobacterium tuberculosis (Mtb). The screening led to the identification of a 6-chloroindole analogue 7j bearing an N-octyl chain and a cycloheptyl moiety, which displayed potent in vitro activity against laboratory and clinical Mtb strains, including a pre-extensively drug-resistant (pre-XDR) isolate. 7j also demonstrated a marked ability to restrict the intracellular growth of Mtb in murine macrophages. Further assays geared toward mechanism of action elucidation have thus far ruled out the involvement of various known promiscuous targets, thereby suggesting that the new indole 7j may inhibit Mtb via a unique mechanism.School of Cancer and Pharmaceutical Sciences King's College London, 150 Stamford StreetTuberculosis Research Laboratory School of Pharmaceutical Sciences Sao Paulo State University (UNESP), Rodovia Araraquara-Jau, km1Drug Discovery and Development Centre (H3D) University of Cape TownSouth African Medical Research Council Drug Discovery and Development Research Unit Department of Chemistry Institute of Infectious Disease and Molecular Medicine University of Cape TownDipartimento di Biotecnologie Chimica e Farmacia Università di Siena, via Aldo Moro 2Tuberculosis Research Laboratory School of Pharmaceutical Sciences Sao Paulo State University (UNESP), Rodovia Araraquara-Jau, km1King's College LondonUniversidade Estadual Paulista (UNESP)University of Cape TownUniversità di SienaSemenya, DorothyTouitou, MeirRibeiro, Camila Maringolo [UNESP]Pavan, Fernando Rogerio [UNESP]Pisano, LucaSingh, VinayakChibale, KellyBano, GeorgToscani, AnitaManetti, FabrizioGianibbi, BeatriceCastagnolo, Daniele2022-05-01T11:23:34Z2022-05-01T11:23:34Z2022-01-13info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article63-69http://dx.doi.org/10.1021/acsmedchemlett.1c00431ACS Medicinal Chemistry Letters, v. 13, n. 1, p. 63-69, 2022.1948-5875http://hdl.handle.net/11449/23389110.1021/acsmedchemlett.1c004312-s2.0-85121053858Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengACS Medicinal Chemistry Lettersinfo:eu-repo/semantics/openAccess2022-05-01T11:23:34Zoai:repositorio.unesp.br:11449/233891Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462022-05-01T11:23:34Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false
dc.title.none.fl_str_mv Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant Mycobacteria
title Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant Mycobacteria
spellingShingle Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant Mycobacteria
Semenya, Dorothy
Antimicrobial resistance
Indole
MDR-TB
Pyrrole
Tuberculosis
XDR-TB
title_short Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant Mycobacteria
title_full Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant Mycobacteria
title_fullStr Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant Mycobacteria
title_full_unstemmed Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant Mycobacteria
title_sort Structural Rigidification of N-Aryl-pyrroles into Indoles Active against Intracellular and Drug-Resistant Mycobacteria
author Semenya, Dorothy
author_facet Semenya, Dorothy
Touitou, Meir
Ribeiro, Camila Maringolo [UNESP]
Pavan, Fernando Rogerio [UNESP]
Pisano, Luca
Singh, Vinayak
Chibale, Kelly
Bano, Georg
Toscani, Anita
Manetti, Fabrizio
Gianibbi, Beatrice
Castagnolo, Daniele
author_role author
author2 Touitou, Meir
Ribeiro, Camila Maringolo [UNESP]
Pavan, Fernando Rogerio [UNESP]
Pisano, Luca
Singh, Vinayak
Chibale, Kelly
Bano, Georg
Toscani, Anita
Manetti, Fabrizio
Gianibbi, Beatrice
Castagnolo, Daniele
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv King's College London
Universidade Estadual Paulista (UNESP)
University of Cape Town
Università di Siena
dc.contributor.author.fl_str_mv Semenya, Dorothy
Touitou, Meir
Ribeiro, Camila Maringolo [UNESP]
Pavan, Fernando Rogerio [UNESP]
Pisano, Luca
Singh, Vinayak
Chibale, Kelly
Bano, Georg
Toscani, Anita
Manetti, Fabrizio
Gianibbi, Beatrice
Castagnolo, Daniele
dc.subject.por.fl_str_mv Antimicrobial resistance
Indole
MDR-TB
Pyrrole
Tuberculosis
XDR-TB
topic Antimicrobial resistance
Indole
MDR-TB
Pyrrole
Tuberculosis
XDR-TB
description A series of indolyl-3-methyleneamines incorporating lipophilic side chains were designed through a structural rigidification approach and synthesized for investigation as new chemical entities against Mycobacterium tuberculosis (Mtb). The screening led to the identification of a 6-chloroindole analogue 7j bearing an N-octyl chain and a cycloheptyl moiety, which displayed potent in vitro activity against laboratory and clinical Mtb strains, including a pre-extensively drug-resistant (pre-XDR) isolate. 7j also demonstrated a marked ability to restrict the intracellular growth of Mtb in murine macrophages. Further assays geared toward mechanism of action elucidation have thus far ruled out the involvement of various known promiscuous targets, thereby suggesting that the new indole 7j may inhibit Mtb via a unique mechanism.
publishDate 2022
dc.date.none.fl_str_mv 2022-05-01T11:23:34Z
2022-05-01T11:23:34Z
2022-01-13
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/10.1021/acsmedchemlett.1c00431
ACS Medicinal Chemistry Letters, v. 13, n. 1, p. 63-69, 2022.
1948-5875
http://hdl.handle.net/11449/233891
10.1021/acsmedchemlett.1c00431
2-s2.0-85121053858
url http://dx.doi.org/10.1021/acsmedchemlett.1c00431
http://hdl.handle.net/11449/233891
identifier_str_mv ACS Medicinal Chemistry Letters, v. 13, n. 1, p. 63-69, 2022.
1948-5875
10.1021/acsmedchemlett.1c00431
2-s2.0-85121053858
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv ACS Medicinal Chemistry Letters
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 63-69
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_ 1799965364151386112

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