Novel harmicines with improved potency against plasmodium
Autor(a) principal: | |
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Data de Publicação: | 2020 |
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/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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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 |
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MDPI |
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reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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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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1799134549017362432 |