Synthesis, activity, toxicity, and in silico studies of new antimycobacterial N-alkyl nitrobenzamides
Autor(a) principal: | |
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Data de Publicação: | 2024 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.14/45522 |
Resumo: | Tuberculosis (TB) is a disease that plagues the frailest members of society. We have developed a family of N-alkyl nitrobenzamides that exhibit promising antitubercular activities and can be considered a structural simplification of known inhibitors of decaprenylphosphoryl-β-D-ribofuranose 2′-oxidase (DprE1), an essential Mycobacterium tuberculosis (Mtb) enzyme and an emergent antitubercular target. Hereby, we report the development of these compounds via a simple synthetic methodology as well as their stability, cytotoxicity, and antitubercular activity. Studying their in vitro activity revealed that the 3,5-dinitro and the 3-nitro-5-trifluoromethyl derivatives were the most active, and within these, the derivatives with intermediate lipophilicities presented the best activities (MIC of 16 ng/mL). Additionally, in an ex vivo macrophage model of infection, the derivatives with chain lengths of six and twelve carbon atoms presented the best results, exhibiting activity profiles comparable to isoniazid. Although the proof is not definite, the assessment of susceptibility over multiple mycobacterial species, together with the structure similarities with known inhibitors of this enzyme, support DprE1 as a likely target of action for the compounds. This idea is also reinforced by the docking studies, where the fit of our more active compounds to the DprE1 binding pocket is very similar to what was observed for known inhibitors like DNB1. |
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7160 |
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Synthesis, activity, toxicity, and in silico studies of new antimycobacterial N-alkyl nitrobenzamidesDprE1MycobacteriaNitrobenzamidesTuberculosisTuberculosis (TB) is a disease that plagues the frailest members of society. We have developed a family of N-alkyl nitrobenzamides that exhibit promising antitubercular activities and can be considered a structural simplification of known inhibitors of decaprenylphosphoryl-β-D-ribofuranose 2′-oxidase (DprE1), an essential Mycobacterium tuberculosis (Mtb) enzyme and an emergent antitubercular target. Hereby, we report the development of these compounds via a simple synthetic methodology as well as their stability, cytotoxicity, and antitubercular activity. Studying their in vitro activity revealed that the 3,5-dinitro and the 3-nitro-5-trifluoromethyl derivatives were the most active, and within these, the derivatives with intermediate lipophilicities presented the best activities (MIC of 16 ng/mL). Additionally, in an ex vivo macrophage model of infection, the derivatives with chain lengths of six and twelve carbon atoms presented the best results, exhibiting activity profiles comparable to isoniazid. Although the proof is not definite, the assessment of susceptibility over multiple mycobacterial species, together with the structure similarities with known inhibitors of this enzyme, support DprE1 as a likely target of action for the compounds. This idea is also reinforced by the docking studies, where the fit of our more active compounds to the DprE1 binding pocket is very similar to what was observed for known inhibitors like DNB1.Veritati - Repositório Institucional da Universidade Católica PortuguesaPais, João P.Antoniuk, OlhaPires, DavidDelgado, TiagoFortuna, AndreiaCosta, Paulo J.Anes, ElsaConstantino, Luis2024-06-18T15:55:04Z2024-05-092024-05-09T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.14/45522eng1424-824710.3390/ph1705060885194399943PMC1112439938794178001231566200001info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-09-06T12:47:42Zoai:repositorio.ucp.pt:10400.14/45522Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-09-06T12:47:42Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Synthesis, activity, toxicity, and in silico studies of new antimycobacterial N-alkyl nitrobenzamides |
title |
Synthesis, activity, toxicity, and in silico studies of new antimycobacterial N-alkyl nitrobenzamides |
spellingShingle |
Synthesis, activity, toxicity, and in silico studies of new antimycobacterial N-alkyl nitrobenzamides Pais, João P. DprE1 Mycobacteria Nitrobenzamides Tuberculosis |
title_short |
Synthesis, activity, toxicity, and in silico studies of new antimycobacterial N-alkyl nitrobenzamides |
title_full |
Synthesis, activity, toxicity, and in silico studies of new antimycobacterial N-alkyl nitrobenzamides |
title_fullStr |
Synthesis, activity, toxicity, and in silico studies of new antimycobacterial N-alkyl nitrobenzamides |
title_full_unstemmed |
Synthesis, activity, toxicity, and in silico studies of new antimycobacterial N-alkyl nitrobenzamides |
title_sort |
Synthesis, activity, toxicity, and in silico studies of new antimycobacterial N-alkyl nitrobenzamides |
author |
Pais, João P. |
author_facet |
Pais, João P. Antoniuk, Olha Pires, David Delgado, Tiago Fortuna, Andreia Costa, Paulo J. Anes, Elsa Constantino, Luis |
author_role |
author |
author2 |
Antoniuk, Olha Pires, David Delgado, Tiago Fortuna, Andreia Costa, Paulo J. Anes, Elsa Constantino, Luis |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Veritati - Repositório Institucional da Universidade Católica Portuguesa |
dc.contributor.author.fl_str_mv |
Pais, João P. Antoniuk, Olha Pires, David Delgado, Tiago Fortuna, Andreia Costa, Paulo J. Anes, Elsa Constantino, Luis |
dc.subject.por.fl_str_mv |
DprE1 Mycobacteria Nitrobenzamides Tuberculosis |
topic |
DprE1 Mycobacteria Nitrobenzamides Tuberculosis |
description |
Tuberculosis (TB) is a disease that plagues the frailest members of society. We have developed a family of N-alkyl nitrobenzamides that exhibit promising antitubercular activities and can be considered a structural simplification of known inhibitors of decaprenylphosphoryl-β-D-ribofuranose 2′-oxidase (DprE1), an essential Mycobacterium tuberculosis (Mtb) enzyme and an emergent antitubercular target. Hereby, we report the development of these compounds via a simple synthetic methodology as well as their stability, cytotoxicity, and antitubercular activity. Studying their in vitro activity revealed that the 3,5-dinitro and the 3-nitro-5-trifluoromethyl derivatives were the most active, and within these, the derivatives with intermediate lipophilicities presented the best activities (MIC of 16 ng/mL). Additionally, in an ex vivo macrophage model of infection, the derivatives with chain lengths of six and twelve carbon atoms presented the best results, exhibiting activity profiles comparable to isoniazid. Although the proof is not definite, the assessment of susceptibility over multiple mycobacterial species, together with the structure similarities with known inhibitors of this enzyme, support DprE1 as a likely target of action for the compounds. This idea is also reinforced by the docking studies, where the fit of our more active compounds to the DprE1 binding pocket is very similar to what was observed for known inhibitors like DNB1. |
publishDate |
2024 |
dc.date.none.fl_str_mv |
2024-06-18T15:55:04Z 2024-05-09 2024-05-09T00:00:00Z |
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://hdl.handle.net/10400.14/45522 |
url |
http://hdl.handle.net/10400.14/45522 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1424-8247 10.3390/ph17050608 85194399943 PMC11124399 38794178 001231566200001 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
mluisa.alvim@gmail.com |
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1817547129647792128 |