Second-generation pterocarpanquinones: synthesis and antileishmanial activity
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | The Journal of venomous animals and toxins including tropical diseases (Online) |
Texto Completo: | http://old.scielo.br/scielo.php?script=sci_arttext&pid=S1678-91992018000100325 |
Resumo: | Abstract Background: Despite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery. In this paper, we report the synthesis and antileishmanial activity of the second generation of pterocarpanoquinones. Methods: The second generation of pterocarpanquinones 2a-f was prepared through a palladium-catalyzed oxyarylation of dihydronaphtalen and chromens with iodolawsone, easily prepared by iodination of lawsone. The spectrum of antileishmanial activity was evaluated in promastigotes and intracellular amastigotes of L. amazonensis, L. braziliensis, and L. infantum. Toxicity was assessed in peritoneal macrophages and selective index calculated by CC50/IC50. Oxidative stress was measured by intracellular ROS levels and mitochondrial membrane potential in treated cells. Results: In this work, we answered two pertinent questions about the structure of the first-generation pterocarpanquinones: the configuration and positions of rings B (pyran) and C (furan) and the presence of oxygen in the B ring. When rings B and C are exchanged, we noted an improvement of the activity against promastigotes and amastigotes of L. amazonensis and promastigotes of L. infantum. As to the oxygen in ring B of the new generation, we observed that the oxygenated compound 2b is approximately twice as active against L. braziliensis promastigotes than its deoxy derivative 2a. Another modification that improved the activity was the addition of the methylenedioxy group. A variation in the susceptibility among species was evident in the clinically relevant form of the parasite, the intracellular amastigote. L. amazonensis was the species most susceptible to novel derivatives, whilst L. infantum was resistant to most of them. The pterocarpanoquinones (2b and 2c) that possess the oxygen atom in ring B showed induction of increased ROS production. Conclusions: The data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents. |
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The Journal of venomous animals and toxins including tropical diseases (Online) |
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Second-generation pterocarpanquinones: synthesis and antileishmanial activityLeishmaniaPterocarpanquinoneLQ-118Phenotypic assayLeishmaniasisDrug discoveryNeglected diseasesAbstract Background: Despite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery. In this paper, we report the synthesis and antileishmanial activity of the second generation of pterocarpanoquinones. Methods: The second generation of pterocarpanquinones 2a-f was prepared through a palladium-catalyzed oxyarylation of dihydronaphtalen and chromens with iodolawsone, easily prepared by iodination of lawsone. The spectrum of antileishmanial activity was evaluated in promastigotes and intracellular amastigotes of L. amazonensis, L. braziliensis, and L. infantum. Toxicity was assessed in peritoneal macrophages and selective index calculated by CC50/IC50. Oxidative stress was measured by intracellular ROS levels and mitochondrial membrane potential in treated cells. Results: In this work, we answered two pertinent questions about the structure of the first-generation pterocarpanquinones: the configuration and positions of rings B (pyran) and C (furan) and the presence of oxygen in the B ring. When rings B and C are exchanged, we noted an improvement of the activity against promastigotes and amastigotes of L. amazonensis and promastigotes of L. infantum. As to the oxygen in ring B of the new generation, we observed that the oxygenated compound 2b is approximately twice as active against L. braziliensis promastigotes than its deoxy derivative 2a. Another modification that improved the activity was the addition of the methylenedioxy group. A variation in the susceptibility among species was evident in the clinically relevant form of the parasite, the intracellular amastigote. L. amazonensis was the species most susceptible to novel derivatives, whilst L. infantum was resistant to most of them. The pterocarpanoquinones (2b and 2c) that possess the oxygen atom in ring B showed induction of increased ROS production. Conclusions: The data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents.Centro de Estudos de Venenos e Animais Peçonhentos (CEVAP/UNESP)2018-01-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersiontext/htmlhttp://old.scielo.br/scielo.php?script=sci_arttext&pid=S1678-91992018000100325Journal of Venomous Animals and Toxins including Tropical Diseases v.24 2018reponame:The Journal of venomous animals and toxins including tropical diseases (Online)instname:Universidade Estadual Paulista (UNESP)instacron:UNESP10.1186/s40409-018-0174-7info:eu-repo/semantics/openAccessFaiões,Viviane dos SantosFrota,Lívia C. R. M. daCunha-Junior,Edézio FerreiraBarcellos,Julio C. F.Silva,Thayssa DaDaher Netto,ChaquipDa-Silva,Silvia Amaral GonçalvesSilva,Alcides J. M. daCosta,Paulo R. R.Torres-Santos,Eduardo Caioeng2018-12-14T00:00:00Zoai:scielo:S1678-91992018000100325Revistahttp://www.scielo.br/jvatitdPUBhttps://old.scielo.br/oai/scielo-oai.php||editorial@jvat.org.br1678-91991678-9180opendoar:2018-12-14T00:00The Journal of venomous animals and toxins including tropical diseases (Online) - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Second-generation pterocarpanquinones: synthesis and antileishmanial activity |
title |
Second-generation pterocarpanquinones: synthesis and antileishmanial activity |
spellingShingle |
Second-generation pterocarpanquinones: synthesis and antileishmanial activity Faiões,Viviane dos Santos Leishmania Pterocarpanquinone LQ-118 Phenotypic assay Leishmaniasis Drug discovery Neglected diseases |
title_short |
Second-generation pterocarpanquinones: synthesis and antileishmanial activity |
title_full |
Second-generation pterocarpanquinones: synthesis and antileishmanial activity |
title_fullStr |
Second-generation pterocarpanquinones: synthesis and antileishmanial activity |
title_full_unstemmed |
Second-generation pterocarpanquinones: synthesis and antileishmanial activity |
title_sort |
Second-generation pterocarpanquinones: synthesis and antileishmanial activity |
author |
Faiões,Viviane dos Santos |
author_facet |
Faiões,Viviane dos Santos Frota,Lívia C. R. M. da Cunha-Junior,Edézio Ferreira Barcellos,Julio C. F. Silva,Thayssa Da Daher Netto,Chaquip Da-Silva,Silvia Amaral Gonçalves Silva,Alcides J. M. da Costa,Paulo R. R. Torres-Santos,Eduardo Caio |
author_role |
author |
author2 |
Frota,Lívia C. R. M. da Cunha-Junior,Edézio Ferreira Barcellos,Julio C. F. Silva,Thayssa Da Daher Netto,Chaquip Da-Silva,Silvia Amaral Gonçalves Silva,Alcides J. M. da Costa,Paulo R. R. Torres-Santos,Eduardo Caio |
author2_role |
author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Faiões,Viviane dos Santos Frota,Lívia C. R. M. da Cunha-Junior,Edézio Ferreira Barcellos,Julio C. F. Silva,Thayssa Da Daher Netto,Chaquip Da-Silva,Silvia Amaral Gonçalves Silva,Alcides J. M. da Costa,Paulo R. R. Torres-Santos,Eduardo Caio |
dc.subject.por.fl_str_mv |
Leishmania Pterocarpanquinone LQ-118 Phenotypic assay Leishmaniasis Drug discovery Neglected diseases |
topic |
Leishmania Pterocarpanquinone LQ-118 Phenotypic assay Leishmaniasis Drug discovery Neglected diseases |
description |
Abstract Background: Despite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery. In this paper, we report the synthesis and antileishmanial activity of the second generation of pterocarpanoquinones. Methods: The second generation of pterocarpanquinones 2a-f was prepared through a palladium-catalyzed oxyarylation of dihydronaphtalen and chromens with iodolawsone, easily prepared by iodination of lawsone. The spectrum of antileishmanial activity was evaluated in promastigotes and intracellular amastigotes of L. amazonensis, L. braziliensis, and L. infantum. Toxicity was assessed in peritoneal macrophages and selective index calculated by CC50/IC50. Oxidative stress was measured by intracellular ROS levels and mitochondrial membrane potential in treated cells. Results: In this work, we answered two pertinent questions about the structure of the first-generation pterocarpanquinones: the configuration and positions of rings B (pyran) and C (furan) and the presence of oxygen in the B ring. When rings B and C are exchanged, we noted an improvement of the activity against promastigotes and amastigotes of L. amazonensis and promastigotes of L. infantum. As to the oxygen in ring B of the new generation, we observed that the oxygenated compound 2b is approximately twice as active against L. braziliensis promastigotes than its deoxy derivative 2a. Another modification that improved the activity was the addition of the methylenedioxy group. A variation in the susceptibility among species was evident in the clinically relevant form of the parasite, the intracellular amastigote. L. amazonensis was the species most susceptible to novel derivatives, whilst L. infantum was resistant to most of them. The pterocarpanoquinones (2b and 2c) that possess the oxygen atom in ring B showed induction of increased ROS production. Conclusions: The data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents. |
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=S1678-91992018000100325 |
url |
http://old.scielo.br/scielo.php?script=sci_arttext&pid=S1678-91992018000100325 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
10.1186/s40409-018-0174-7 |
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 |
Centro de Estudos de Venenos e Animais Peçonhentos (CEVAP/UNESP) |
publisher.none.fl_str_mv |
Centro de Estudos de Venenos e Animais Peçonhentos (CEVAP/UNESP) |
dc.source.none.fl_str_mv |
Journal of Venomous Animals and Toxins including Tropical Diseases v.24 2018 reponame:The Journal of venomous animals and toxins including tropical diseases (Online) instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
The Journal of venomous animals and toxins including tropical diseases (Online) |
collection |
The Journal of venomous animals and toxins including tropical diseases (Online) |
repository.name.fl_str_mv |
The Journal of venomous animals and toxins including tropical diseases (Online) - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
||editorial@jvat.org.br |
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1748958540520751104 |