Novel harmicines with improved potency against plasmodium

Detalhes bibliográficos
Autor(a) principal: Marinović, Marina
Data de Publicação: 2020
Outros Autores: Perković, Ivana, Fontinha, Diana, Prudêncio, Miguel, Held, Jana, Pessanha de Carvalho, Lais, Tandarić, Tana, Vianello, Robert, Zorc, Branka, Rajić, Zrinka
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/48331
Resumo: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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spelling Novel harmicines with improved potency against plasmodiumP. bergheiP. falciparumPfHsp90AmideAntiplasmodial activityCinnamic acidHarmineMolecular dynamics simulations© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Harmicines represent hybrid compounds composed of β-carboline alkaloid harmine and cinnamic acid derivatives (CADs). In this paper we report the synthesis of amide-type harmicines and the evaluation of their biological activity. N-harmicines 5a–f and O-harmicines 6a–h were prepared by a straightforward synthetic procedure, from harmine-based amines and CADs using standard coupling conditions, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIEA). Amide-type harmicines exerted remarkable activity against the erythrocytic stage of P. falciparum, in low submicromolar concentrations, which was significantly more pronounced compared to their antiplasmodial activity against the hepatic stages of P. berghei. Furthermore, a cytotoxicity assay against the human liver hepatocellular carcinoma cell line (HepG2) revealed favorable selectivity indices of the most active harmicines. Molecular dynamics simulations demonstrated the binding of ligands within the ATP binding site of PfHsp90, while the calculated binding free energies confirmed higher activity of N-harmicines 5 over their O-substituted analogues 6. Amino acids predominantly affecting the binding were identified, which provided guidelines for the further derivatization of the harmine framework towards more efficient agents.The authors acknowledge the financial support of the Croatian Science Foundation (research project UIP-2017-05-5160), the University of Zagreb (support for 2019), and Fundação para a Ciência e Tecnologia, Portugal (FCT) (grant 02/SAICT/2017/29550). The work of doctoral student M. Marinović was fully supported by the Young researcher’s career development project—training of doctoral students of the Croatian Science Foundation, founded by the European Union through the European Social Fund.MDPIRepositório da Universidade de LisboaMarinović, MarinaPerković, IvanaFontinha, DianaPrudêncio, MiguelHeld, JanaPessanha de Carvalho, LaisTandarić, TanaVianello, RobertZorc, BrankaRajić, Zrinka2021-06-04T13:01:54Z20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/48331engMolecules 2020, 25, 437610.3390/molecules251943761420-3049info: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:RCAAP2023-11-08T16:51:39Zoai:repositorio.ul.pt:10451/48331Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:00:13.793460Repositório 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 Novel harmicines with improved potency against plasmodium
title Novel harmicines with improved potency against plasmodium
spellingShingle Novel harmicines with improved potency against plasmodium
Marinović, Marina
P. berghei
P. falciparum
PfHsp90
Amide
Antiplasmodial activity
Cinnamic acid
Harmine
Molecular dynamics simulations
title_short Novel harmicines with improved potency against plasmodium
title_full Novel harmicines with improved potency against plasmodium
title_fullStr Novel harmicines with improved potency against plasmodium
title_full_unstemmed Novel harmicines with improved potency against plasmodium
title_sort Novel harmicines with improved potency against plasmodium
author Marinović, Marina
author_facet Marinović, Marina
Perković, Ivana
Fontinha, Diana
Prudêncio, Miguel
Held, Jana
Pessanha de Carvalho, Lais
Tandarić, Tana
Vianello, Robert
Zorc, Branka
Rajić, Zrinka
author_role author
author2 Perković, Ivana
Fontinha, Diana
Prudêncio, Miguel
Held, Jana
Pessanha de Carvalho, Lais
Tandarić, Tana
Vianello, Robert
Zorc, Branka
Rajić, Zrinka
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Marinović, Marina
Perković, Ivana
Fontinha, Diana
Prudêncio, Miguel
Held, Jana
Pessanha de Carvalho, Lais
Tandarić, Tana
Vianello, Robert
Zorc, Branka
Rajić, Zrinka
dc.subject.por.fl_str_mv P. berghei
P. falciparum
PfHsp90
Amide
Antiplasmodial activity
Cinnamic acid
Harmine
Molecular dynamics simulations
topic P. berghei
P. falciparum
PfHsp90
Amide
Antiplasmodial activity
Cinnamic acid
Harmine
Molecular dynamics simulations
description © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-01-01T00:00:00Z
2021-06-04T13:01:54Z
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/10451/48331
url http://hdl.handle.net/10451/48331
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Molecules 2020, 25, 4376
10.3390/molecules25194376
1420-3049
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.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
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
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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
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