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New Trifluoromethyl Triazolopyrimidines as Anti-Plasmodiumfalciparum Agents
According to the World Health Organization, half of the World’s population, approximately 3.3 billion people, is at risk for developing malaria. Nearly 700,000 deaths each year are associated with the disease. Control of the disease in humans still relies on chemotherapy. Drug resistance is a limiti...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6268855/ https://www.ncbi.nlm.nih.gov/pubmed/22781441 http://dx.doi.org/10.3390/molecules17078285 |
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author | Boechat, Núbia Pinheiro, Luiz C. S. Silva, Thiago S. Aguiar, Anna C. C. Carvalho, Alcione S. Bastos, Monica M. Costa, Carolina C. P. Pinheiro, Sergio Pinto, Angelo C. Mendonça, Jorge S. Dutra, Karen D. B. Valverde, Alessandra L. Santos-Filho, Osvaldo A. Ceravolo, Isabela P. Krettli, Antoniana U. |
author_facet | Boechat, Núbia Pinheiro, Luiz C. S. Silva, Thiago S. Aguiar, Anna C. C. Carvalho, Alcione S. Bastos, Monica M. Costa, Carolina C. P. Pinheiro, Sergio Pinto, Angelo C. Mendonça, Jorge S. Dutra, Karen D. B. Valverde, Alessandra L. Santos-Filho, Osvaldo A. Ceravolo, Isabela P. Krettli, Antoniana U. |
author_sort | Boechat, Núbia |
collection | PubMed |
description | According to the World Health Organization, half of the World’s population, approximately 3.3 billion people, is at risk for developing malaria. Nearly 700,000 deaths each year are associated with the disease. Control of the disease in humans still relies on chemotherapy. Drug resistance is a limiting factor, and the search for new drugs is important. We have designed and synthesized new 2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidine derivatives based on bioisosteric replacement of functional groups on the anti-malarial compounds mefloquine and amodiaquine. This approach enabled us to investigate the impact of: (i) ring bioisosteric replacement; (ii) a CF(3) group substituted at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine scaffold and (iii) a range of amines as substituents at the 7-position of the of heterocyclic ring; on in vitro activity against Plasmodium falciparum. According to docking simulations, the synthesized compounds are able to interact with P. falciparum dihydroorotate dehydrogenase (PfDHODH) through strong hydrogen bonds. The presence of a trifluoromethyl group at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine ring led to increased drug activity. Thirteen compounds were found to be active, with IC(50) values ranging from 0.023 to 20 µM in the anti-HRP2 and hypoxanthine assays. The selectivity index (SI) of the most active derivatives 5, 8, 11 and 16 was found to vary from 1,003 to 18,478. |
format | Online Article Text |
id | pubmed-6268855 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62688552018-12-12 New Trifluoromethyl Triazolopyrimidines as Anti-Plasmodiumfalciparum Agents Boechat, Núbia Pinheiro, Luiz C. S. Silva, Thiago S. Aguiar, Anna C. C. Carvalho, Alcione S. Bastos, Monica M. Costa, Carolina C. P. Pinheiro, Sergio Pinto, Angelo C. Mendonça, Jorge S. Dutra, Karen D. B. Valverde, Alessandra L. Santos-Filho, Osvaldo A. Ceravolo, Isabela P. Krettli, Antoniana U. Molecules Article According to the World Health Organization, half of the World’s population, approximately 3.3 billion people, is at risk for developing malaria. Nearly 700,000 deaths each year are associated with the disease. Control of the disease in humans still relies on chemotherapy. Drug resistance is a limiting factor, and the search for new drugs is important. We have designed and synthesized new 2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidine derivatives based on bioisosteric replacement of functional groups on the anti-malarial compounds mefloquine and amodiaquine. This approach enabled us to investigate the impact of: (i) ring bioisosteric replacement; (ii) a CF(3) group substituted at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine scaffold and (iii) a range of amines as substituents at the 7-position of the of heterocyclic ring; on in vitro activity against Plasmodium falciparum. According to docking simulations, the synthesized compounds are able to interact with P. falciparum dihydroorotate dehydrogenase (PfDHODH) through strong hydrogen bonds. The presence of a trifluoromethyl group at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine ring led to increased drug activity. Thirteen compounds were found to be active, with IC(50) values ranging from 0.023 to 20 µM in the anti-HRP2 and hypoxanthine assays. The selectivity index (SI) of the most active derivatives 5, 8, 11 and 16 was found to vary from 1,003 to 18,478. MDPI 2012-07-10 /pmc/articles/PMC6268855/ /pubmed/22781441 http://dx.doi.org/10.3390/molecules17078285 Text en © 2012 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Boechat, Núbia Pinheiro, Luiz C. S. Silva, Thiago S. Aguiar, Anna C. C. Carvalho, Alcione S. Bastos, Monica M. Costa, Carolina C. P. Pinheiro, Sergio Pinto, Angelo C. Mendonça, Jorge S. Dutra, Karen D. B. Valverde, Alessandra L. Santos-Filho, Osvaldo A. Ceravolo, Isabela P. Krettli, Antoniana U. New Trifluoromethyl Triazolopyrimidines as Anti-Plasmodiumfalciparum Agents |
title | New Trifluoromethyl Triazolopyrimidines as Anti-Plasmodiumfalciparum Agents |
title_full | New Trifluoromethyl Triazolopyrimidines as Anti-Plasmodiumfalciparum Agents |
title_fullStr | New Trifluoromethyl Triazolopyrimidines as Anti-Plasmodiumfalciparum Agents |
title_full_unstemmed | New Trifluoromethyl Triazolopyrimidines as Anti-Plasmodiumfalciparum Agents |
title_short | New Trifluoromethyl Triazolopyrimidines as Anti-Plasmodiumfalciparum Agents |
title_sort | new trifluoromethyl triazolopyrimidines as anti-plasmodiumfalciparum agents |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6268855/ https://www.ncbi.nlm.nih.gov/pubmed/22781441 http://dx.doi.org/10.3390/molecules17078285 |
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