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/11449/218986
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 MycobacteriaTuberculosisMDR-TBXDR-TBIndolePyrroleAntimicrobial resistanceA 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.South African National Research Foundation-SARChIUniversity of LondonSouth African Medical Research Council (SAMRC)South African Department of Science and InnovationSouth African National Research FoundationFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Kings Coll London, Sch Canc & Pharmaceut Sci, London SE1 9NH, EnglandSao Paulo State Univ UNESP, TB Res Lab, Sch Pharmaceut Sci, BR-14800903 Araraquara, SP, BrazilUniv Cape Town, Drug Discovery & Dev Ctr H3D, ZA-7701 Rondebosch, South AfricaUniv Cape Town, South African Med Res Council Drug Discovery & De, Dept Chem, ZA-7701 Rondebosch, South AfricaUniv Cape Town, Inst Infect Dis & Mol Med, ZA-7701 Rondebosch, South AfricaUniv Siena, Dipartimento Biotecnol Chim & Farm, I-53100 Siena, ItalySao Paulo State Univ UNESP, TB Res Lab, Sch Pharmaceut Sci, BR-14800903 Araraquara, SP, BrazilAmer Chemical SocKings Coll LondonUniversidade Estadual Paulista (UNESP)Univ Cape TownUniv SienaSemenya, DorothyTouitou, MeirRibeiro, Camila Maringolo [UNESP]Pavan, Fernando Rogerio [UNESP]Pisano, LucaSingh, VinayakChibale, KellyBano, GeorgToscani, AnitaManetti, FabrizioGianibbi, BeatriceCastagnolo, Daniele2022-04-28T18:27:38Z2022-04-28T18:27:38Z2022-01-13info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article63-69http://dx.doi.org/10.1021/acsmedchemlett.1c00431Acs Medicinal Chemistry Letters. Washington: Amer Chemical Soc, v. 13, n. 1, p. 63-69, 2022.1948-5875http://hdl.handle.net/11449/21898610.1021/acsmedchemlett.1c00431WOS:000766538900006Web of Sciencereponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengAcs Medicinal Chemistry Lettersinfo:eu-repo/semantics/openAccess2022-04-28T18:27:38Zoai:repositorio.unesp.br:11449/218986Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462022-04-28T18:27:38Repositório 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
Tuberculosis
MDR-TB
XDR-TB
Indole
Pyrrole
Antimicrobial resistance
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 Kings Coll London
Universidade Estadual Paulista (UNESP)
Univ Cape Town
Univ 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 Tuberculosis
MDR-TB
XDR-TB
Indole
Pyrrole
Antimicrobial resistance
topic Tuberculosis
MDR-TB
XDR-TB
Indole
Pyrrole
Antimicrobial resistance
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 2022-04-28T18:27:38Z
2022-04-28T18:27:38Z
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. Washington: Amer Chemical Soc, v. 13, n. 1, p. 63-69, 2022.
1948-5875
http://hdl.handle.net/11449/218986
10.1021/acsmedchemlett.1c00431
WOS:000766538900006
url http://dx.doi.org/10.1021/acsmedchemlett.1c00431
http://hdl.handle.net/11449/218986
identifier_str_mv Acs Medicinal Chemistry Letters. Washington: Amer Chemical Soc, v. 13, n. 1, p. 63-69, 2022.
1948-5875
10.1021/acsmedchemlett.1c00431
WOS:000766538900006
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.publisher.none.fl_str_mv Amer Chemical Soc
publisher.none.fl_str_mv Amer Chemical Soc
dc.source.none.fl_str_mv Web of Science
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_ 1799965163439259648

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