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Second-generation pterocarpanquinones: synthesis and antileishmanial activity
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 esse...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263544/ https://www.ncbi.nlm.nih.gov/pubmed/30519257 http://dx.doi.org/10.1186/s40409-018-0174-7 |
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author | Faiões, Viviane dos Santos da Frota, Lívia C. R. M. Cunha-Junior, Edézio Ferreira Barcellos, Julio C. F. Da Silva, Thayssa Netto, Chaquip Daher Da-Silva, Silvia Amaral Gonçalves da Silva, Alcides J. M. Costa, Paulo R. R. Torres-Santos, Eduardo Caio |
author_facet | Faiões, Viviane dos Santos da Frota, Lívia C. R. M. Cunha-Junior, Edézio Ferreira Barcellos, Julio C. F. Da Silva, Thayssa Netto, Chaquip Daher Da-Silva, Silvia Amaral Gonçalves da Silva, Alcides J. M. Costa, Paulo R. R. Torres-Santos, Eduardo Caio |
author_sort | Faiões, Viviane dos Santos |
collection | PubMed |
description | 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 CC(50)/IC(50). 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. |
format | Online Article Text |
id | pubmed-6263544 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-62635442018-12-05 Second-generation pterocarpanquinones: synthesis and antileishmanial activity Faiões, Viviane dos Santos da Frota, Lívia C. R. M. Cunha-Junior, Edézio Ferreira Barcellos, Julio C. F. Da Silva, Thayssa Netto, Chaquip Daher Da-Silva, Silvia Amaral Gonçalves da Silva, Alcides J. M. Costa, Paulo R. R. Torres-Santos, Eduardo Caio J Venom Anim Toxins Incl Trop Dis Research 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 CC(50)/IC(50). 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. BioMed Central 2018-11-29 /pmc/articles/PMC6263544/ /pubmed/30519257 http://dx.doi.org/10.1186/s40409-018-0174-7 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Faiões, Viviane dos Santos da Frota, Lívia C. R. M. Cunha-Junior, Edézio Ferreira Barcellos, Julio C. F. Da Silva, Thayssa Netto, Chaquip Daher Da-Silva, Silvia Amaral Gonçalves da Silva, Alcides J. M. Costa, Paulo R. R. Torres-Santos, Eduardo Caio Second-generation pterocarpanquinones: synthesis and antileishmanial activity |
title | 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_short | Second-generation pterocarpanquinones: synthesis and antileishmanial activity |
title_sort | second-generation pterocarpanquinones: synthesis and antileishmanial activity |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263544/ https://www.ncbi.nlm.nih.gov/pubmed/30519257 http://dx.doi.org/10.1186/s40409-018-0174-7 |
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