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Synthesis and Structure–Activity Relationship of Dehydrodieugenol B Neolignans against Trypanosoma cruzi
[Image: see text] Trypanosoma cruzi is the etiologic agent of Chagas disease, which affects over seven million people, especially in developing countries. Undesirable side effects are frequently associated with current therapies, which are typically ineffective in the treatment of all stages of the...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670487/ https://www.ncbi.nlm.nih.gov/pubmed/33047947 http://dx.doi.org/10.1021/acsinfecdis.0c00523 |
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author | Sear, Claire E. Pieper, Pauline Amaral, Maiara Romanelli, Maiara M. Costa-Silva, Thais A. Haugland, Marius M. Tate, Joseph A. Lago, João H. G. Tempone, Andre G. Anderson, Edward A. |
author_facet | Sear, Claire E. Pieper, Pauline Amaral, Maiara Romanelli, Maiara M. Costa-Silva, Thais A. Haugland, Marius M. Tate, Joseph A. Lago, João H. G. Tempone, Andre G. Anderson, Edward A. |
author_sort | Sear, Claire E. |
collection | PubMed |
description | [Image: see text] Trypanosoma cruzi is the etiologic agent of Chagas disease, which affects over seven million people, especially in developing countries. Undesirable side effects are frequently associated with current therapies, which are typically ineffective in the treatment of all stages of the disease. Here, we report the first synthesis of the neolignan dehydrodieugenol B, a natural product recently shown to exhibit activity against T. cruzi. Using this strategy, a series of synthetic analogues were prepared to explore structure–activity relationships. The in vitro antiparasitic activities of these analogues revealed a wide tolerance of modifications and substituent deletions, with maintained or improved bioactivities against the amastigote forms of the parasite (50% inhibitory concentration (IC(50)) of 4–63 μM) and no mammalian toxicity (50% cytotoxic concentration (CC(50)) of >200 μM). Five of these analogues meet the Drugs for Neglected Disease Initiative (DNDi) “hit criteria” for Chagas disease. This work has enabled the identification of key structural features of the natural product and sites where scaffold modification is tolerated. |
format | Online Article Text |
id | pubmed-7670487 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-76704872020-11-17 Synthesis and Structure–Activity Relationship of Dehydrodieugenol B Neolignans against Trypanosoma cruzi Sear, Claire E. Pieper, Pauline Amaral, Maiara Romanelli, Maiara M. Costa-Silva, Thais A. Haugland, Marius M. Tate, Joseph A. Lago, João H. G. Tempone, Andre G. Anderson, Edward A. ACS Infect Dis [Image: see text] Trypanosoma cruzi is the etiologic agent of Chagas disease, which affects over seven million people, especially in developing countries. Undesirable side effects are frequently associated with current therapies, which are typically ineffective in the treatment of all stages of the disease. Here, we report the first synthesis of the neolignan dehydrodieugenol B, a natural product recently shown to exhibit activity against T. cruzi. Using this strategy, a series of synthetic analogues were prepared to explore structure–activity relationships. The in vitro antiparasitic activities of these analogues revealed a wide tolerance of modifications and substituent deletions, with maintained or improved bioactivities against the amastigote forms of the parasite (50% inhibitory concentration (IC(50)) of 4–63 μM) and no mammalian toxicity (50% cytotoxic concentration (CC(50)) of >200 μM). Five of these analogues meet the Drugs for Neglected Disease Initiative (DNDi) “hit criteria” for Chagas disease. This work has enabled the identification of key structural features of the natural product and sites where scaffold modification is tolerated. American Chemical Society 2020-10-13 2020-11-13 /pmc/articles/PMC7670487/ /pubmed/33047947 http://dx.doi.org/10.1021/acsinfecdis.0c00523 Text en © 2020 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Sear, Claire E. Pieper, Pauline Amaral, Maiara Romanelli, Maiara M. Costa-Silva, Thais A. Haugland, Marius M. Tate, Joseph A. Lago, João H. G. Tempone, Andre G. Anderson, Edward A. Synthesis and Structure–Activity Relationship of Dehydrodieugenol B Neolignans against Trypanosoma cruzi |
title | Synthesis and Structure–Activity Relationship
of Dehydrodieugenol B Neolignans against Trypanosoma cruzi |
title_full | Synthesis and Structure–Activity Relationship
of Dehydrodieugenol B Neolignans against Trypanosoma cruzi |
title_fullStr | Synthesis and Structure–Activity Relationship
of Dehydrodieugenol B Neolignans against Trypanosoma cruzi |
title_full_unstemmed | Synthesis and Structure–Activity Relationship
of Dehydrodieugenol B Neolignans against Trypanosoma cruzi |
title_short | Synthesis and Structure–Activity Relationship
of Dehydrodieugenol B Neolignans against Trypanosoma cruzi |
title_sort | synthesis and structure–activity relationship
of dehydrodieugenol b neolignans against trypanosoma cruzi |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670487/ https://www.ncbi.nlm.nih.gov/pubmed/33047947 http://dx.doi.org/10.1021/acsinfecdis.0c00523 |
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