Synthesis, activity, toxicity, and in silico studies of new antimycobacterial N-alkyl nitrobenzamides

Detalhes bibliográficos
Autor(a) principal: Pais, João P.
Data de Publicação: 2024
Outros Autores: Antoniuk, Olha, Pires, David, Delgado, Tiago, Fortuna, Andreia, Costa, Paulo J., Anes, Elsa, Constantino, Luis
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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spelling 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
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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
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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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