2,3,8-Trisubstituted Quinolines with Antimalarial Activity
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Anais da Academia Brasileira de Ciências (Online) |
Texto Completo: | http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0001-37652018000301215 |
Resumo: | ABSTRACT Combination therapy drugs are considered a fundamental way to control malaria as it mimimizes the risk of emergence of resistance to the individual partner drugs. Consequently, this type of therapy constitutes a driving force for the discovery of new drugs with different modes of action, since this will provide options for combining different drugs to achieve the optimum antimalarial treatment. In this context, a 2,3,8-trisubstitued quinoline compound was found in a high throughput screen (HTS) to show an excellent inhibition of P. falciparum NF54 (IC50 = 22 nM) and low cytotoxicity. We performed a detailed evaluation of the substituents to improve the metabolic stability and solubility liabilities of the original hit and identified derivatives with enhanced physicochemical and/or PK properties and that maintained biological activity. However the high potency was not retained on testing against drug resistant plasmodium strains. |
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Anais da Academia Brasileira de Ciências (Online) |
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2,3,8-Trisubstituted Quinolines with Antimalarial Activityantimalarial activitytrisubstituted quinolineSARresistanceABSTRACT Combination therapy drugs are considered a fundamental way to control malaria as it mimimizes the risk of emergence of resistance to the individual partner drugs. Consequently, this type of therapy constitutes a driving force for the discovery of new drugs with different modes of action, since this will provide options for combining different drugs to achieve the optimum antimalarial treatment. In this context, a 2,3,8-trisubstitued quinoline compound was found in a high throughput screen (HTS) to show an excellent inhibition of P. falciparum NF54 (IC50 = 22 nM) and low cytotoxicity. We performed a detailed evaluation of the substituents to improve the metabolic stability and solubility liabilities of the original hit and identified derivatives with enhanced physicochemical and/or PK properties and that maintained biological activity. However the high potency was not retained on testing against drug resistant plasmodium strains.Academia Brasileira de Ciências2018-01-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersiontext/htmlhttp://old.scielo.br/scielo.php?script=sci_arttext&pid=S0001-37652018000301215Anais da Academia Brasileira de Ciências v.90 n.1 suppl.2 2018reponame:Anais da Academia Brasileira de Ciências (Online)instname:Academia Brasileira de Ciências (ABC)instacron:ABC10.1590/0001-3765201820170820info:eu-repo/semantics/openAccessMARTINEZ,PABLO D.G.KRAKE,SUSANN H.POGGI,MAITIA L.CAMPBELL,SIMON F.WILLIS,PAUL A.DIAS,LUIZ C.eng2018-05-28T00:00:00Zoai:scielo:S0001-37652018000301215Revistahttp://www.scielo.br/aabchttps://old.scielo.br/oai/scielo-oai.php||aabc@abc.org.br1678-26900001-3765opendoar:2018-05-28T00:00Anais da Academia Brasileira de Ciências (Online) - Academia Brasileira de Ciências (ABC)false |
dc.title.none.fl_str_mv |
2,3,8-Trisubstituted Quinolines with Antimalarial Activity |
title |
2,3,8-Trisubstituted Quinolines with Antimalarial Activity |
spellingShingle |
2,3,8-Trisubstituted Quinolines with Antimalarial Activity MARTINEZ,PABLO D.G. antimalarial activity trisubstituted quinoline SAR resistance |
title_short |
2,3,8-Trisubstituted Quinolines with Antimalarial Activity |
title_full |
2,3,8-Trisubstituted Quinolines with Antimalarial Activity |
title_fullStr |
2,3,8-Trisubstituted Quinolines with Antimalarial Activity |
title_full_unstemmed |
2,3,8-Trisubstituted Quinolines with Antimalarial Activity |
title_sort |
2,3,8-Trisubstituted Quinolines with Antimalarial Activity |
author |
MARTINEZ,PABLO D.G. |
author_facet |
MARTINEZ,PABLO D.G. KRAKE,SUSANN H. POGGI,MAITIA L. CAMPBELL,SIMON F. WILLIS,PAUL A. DIAS,LUIZ C. |
author_role |
author |
author2 |
KRAKE,SUSANN H. POGGI,MAITIA L. CAMPBELL,SIMON F. WILLIS,PAUL A. DIAS,LUIZ C. |
author2_role |
author author author author author |
dc.contributor.author.fl_str_mv |
MARTINEZ,PABLO D.G. KRAKE,SUSANN H. POGGI,MAITIA L. CAMPBELL,SIMON F. WILLIS,PAUL A. DIAS,LUIZ C. |
dc.subject.por.fl_str_mv |
antimalarial activity trisubstituted quinoline SAR resistance |
topic |
antimalarial activity trisubstituted quinoline SAR resistance |
description |
ABSTRACT Combination therapy drugs are considered a fundamental way to control malaria as it mimimizes the risk of emergence of resistance to the individual partner drugs. Consequently, this type of therapy constitutes a driving force for the discovery of new drugs with different modes of action, since this will provide options for combining different drugs to achieve the optimum antimalarial treatment. In this context, a 2,3,8-trisubstitued quinoline compound was found in a high throughput screen (HTS) to show an excellent inhibition of P. falciparum NF54 (IC50 = 22 nM) and low cytotoxicity. We performed a detailed evaluation of the substituents to improve the metabolic stability and solubility liabilities of the original hit and identified derivatives with enhanced physicochemical and/or PK properties and that maintained biological activity. However the high potency was not retained on testing against drug resistant plasmodium strains. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-01-01 |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0001-37652018000301215 |
url |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0001-37652018000301215 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
10.1590/0001-3765201820170820 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
text/html |
dc.publisher.none.fl_str_mv |
Academia Brasileira de Ciências |
publisher.none.fl_str_mv |
Academia Brasileira de Ciências |
dc.source.none.fl_str_mv |
Anais da Academia Brasileira de Ciências v.90 n.1 suppl.2 2018 reponame:Anais da Academia Brasileira de Ciências (Online) instname:Academia Brasileira de Ciências (ABC) instacron:ABC |
instname_str |
Academia Brasileira de Ciências (ABC) |
instacron_str |
ABC |
institution |
ABC |
reponame_str |
Anais da Academia Brasileira de Ciências (Online) |
collection |
Anais da Academia Brasileira de Ciências (Online) |
repository.name.fl_str_mv |
Anais da Academia Brasileira de Ciências (Online) - Academia Brasileira de Ciências (ABC) |
repository.mail.fl_str_mv |
||aabc@abc.org.br |
_version_ |
1754302866569297920 |