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Antiplasmodial profile of selected compounds from Malaria Box: in vitro evaluation, speed of action and drug combination studies
BACKGROUND: Artemisinin-based combination therapy (ACT) is used as the first-line treatment of uncomplicated malaria caused by the Plasmodium falciparum parasite and chloroquine-resistant Plasmodium vivax parasites. Evidence of resistance to ACT has been reported in Cambodia, and without new and eff...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938011/ https://www.ncbi.nlm.nih.gov/pubmed/31888654 http://dx.doi.org/10.1186/s12936-019-3069-3 |
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author | de Souza, Guilherme Eduardo Bueno, Renata Vieira de Souza, Juliana Oliveira Zanini, Camila Lima Cruz, Fábio Cardoso Oliva, Glaucius Guido, Rafael Victório Carvalho Aguiar, Anna Caroline Campos |
author_facet | de Souza, Guilherme Eduardo Bueno, Renata Vieira de Souza, Juliana Oliveira Zanini, Camila Lima Cruz, Fábio Cardoso Oliva, Glaucius Guido, Rafael Victório Carvalho Aguiar, Anna Caroline Campos |
author_sort | de Souza, Guilherme Eduardo |
collection | PubMed |
description | BACKGROUND: Artemisinin-based combination therapy (ACT) is used as the first-line treatment of uncomplicated malaria caused by the Plasmodium falciparum parasite and chloroquine-resistant Plasmodium vivax parasites. Evidence of resistance to ACT has been reported in Cambodia, and without new and effective anti-malarial agents, malaria burden and mortality will rise. METHODS: The used MolPrint 2D fingerprints and the Tanimoto similarity index were used to perform a structural similarity search within the Malaria Box collection to select diverse molecular scaffolds that are different from artesunate. Next, the inhibitory potency against the P. falciparum 3D7 strain (SYBR Green I inhibition assay) and the cytotoxicity against HepG2 cells (MTT and neutral red assays) were evaluated. Then, the speed of action, the combination profile of selected inhibitors with artesunate, and the P. berghei in vivo activity of the best compounds were assessed. RESULTS: A set of 11 structurally diverse compounds from the Malaria Box with a similarity threshold of less than 0.05 was selected and compared with artesunate. The in vitro inhibitory activity of each compound confirmed the reported potencies (IC(50) values ranging from 0.005 to 1 µM). The cytotoxicity of each selected compound was evaluated and used to calculate the selectivity index (SI values ranging from 15.1 to 6100). Next, both the speed of action and the combination profile of each compound with artesunate was assessed. Acridine, thiazolopyrimidine, quinoxaline, benzimidazole, thiophene, benzodiazepine, isoxazole and pyrimidoindole derivatives showed fast in vitro inhibitory activity of parasite growth, whereas hydrazinobenzimidazole, indenopyridazinone and naphthalenone derivatives were slow-acting in vitro inhibitors. Combinatory profile evaluation indicated that thiazolopyrimidinone and benzodiazepine derivatives have an additive profile, suggesting that the combination of these inhibitors with artesunate is favourable for in vitro inhibitory activity. The remaining compounds showed an antagonistic combinatory profile with artesunate. The collected data indicated that the indenopyridazinone derivative, a bc(1) complex inhibitor, had a similar association profile in combination with proguanil when compared to atovaquone combined with proguanil, thereby corroborating the correlation between the molecular target and the combination profile. Lastly, the in vivo activity of the thiazolopyrimidinone and benzodiazepine derivatives were assessed. Both compounds showed oral efficacy at 50 mg/kg in a mouse model of Plasmodium berghei malaria (64% and 40% reduction in parasitaemia on day 5 post-infection, respectively). CONCLUSIONS: The findings in this paper shed light on the relationship among the speed of action, molecular target and combinatory profile and identified new hits with in vivo activity as candidates for anti-malarial combination therapy. |
format | Online Article Text |
id | pubmed-6938011 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-69380112019-12-31 Antiplasmodial profile of selected compounds from Malaria Box: in vitro evaluation, speed of action and drug combination studies de Souza, Guilherme Eduardo Bueno, Renata Vieira de Souza, Juliana Oliveira Zanini, Camila Lima Cruz, Fábio Cardoso Oliva, Glaucius Guido, Rafael Victório Carvalho Aguiar, Anna Caroline Campos Malar J Research BACKGROUND: Artemisinin-based combination therapy (ACT) is used as the first-line treatment of uncomplicated malaria caused by the Plasmodium falciparum parasite and chloroquine-resistant Plasmodium vivax parasites. Evidence of resistance to ACT has been reported in Cambodia, and without new and effective anti-malarial agents, malaria burden and mortality will rise. METHODS: The used MolPrint 2D fingerprints and the Tanimoto similarity index were used to perform a structural similarity search within the Malaria Box collection to select diverse molecular scaffolds that are different from artesunate. Next, the inhibitory potency against the P. falciparum 3D7 strain (SYBR Green I inhibition assay) and the cytotoxicity against HepG2 cells (MTT and neutral red assays) were evaluated. Then, the speed of action, the combination profile of selected inhibitors with artesunate, and the P. berghei in vivo activity of the best compounds were assessed. RESULTS: A set of 11 structurally diverse compounds from the Malaria Box with a similarity threshold of less than 0.05 was selected and compared with artesunate. The in vitro inhibitory activity of each compound confirmed the reported potencies (IC(50) values ranging from 0.005 to 1 µM). The cytotoxicity of each selected compound was evaluated and used to calculate the selectivity index (SI values ranging from 15.1 to 6100). Next, both the speed of action and the combination profile of each compound with artesunate was assessed. Acridine, thiazolopyrimidine, quinoxaline, benzimidazole, thiophene, benzodiazepine, isoxazole and pyrimidoindole derivatives showed fast in vitro inhibitory activity of parasite growth, whereas hydrazinobenzimidazole, indenopyridazinone and naphthalenone derivatives were slow-acting in vitro inhibitors. Combinatory profile evaluation indicated that thiazolopyrimidinone and benzodiazepine derivatives have an additive profile, suggesting that the combination of these inhibitors with artesunate is favourable for in vitro inhibitory activity. The remaining compounds showed an antagonistic combinatory profile with artesunate. The collected data indicated that the indenopyridazinone derivative, a bc(1) complex inhibitor, had a similar association profile in combination with proguanil when compared to atovaquone combined with proguanil, thereby corroborating the correlation between the molecular target and the combination profile. Lastly, the in vivo activity of the thiazolopyrimidinone and benzodiazepine derivatives were assessed. Both compounds showed oral efficacy at 50 mg/kg in a mouse model of Plasmodium berghei malaria (64% and 40% reduction in parasitaemia on day 5 post-infection, respectively). CONCLUSIONS: The findings in this paper shed light on the relationship among the speed of action, molecular target and combinatory profile and identified new hits with in vivo activity as candidates for anti-malarial combination therapy. BioMed Central 2019-12-30 /pmc/articles/PMC6938011/ /pubmed/31888654 http://dx.doi.org/10.1186/s12936-019-3069-3 Text en © The Author(s) 2019 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data. |
spellingShingle | Research de Souza, Guilherme Eduardo Bueno, Renata Vieira de Souza, Juliana Oliveira Zanini, Camila Lima Cruz, Fábio Cardoso Oliva, Glaucius Guido, Rafael Victório Carvalho Aguiar, Anna Caroline Campos Antiplasmodial profile of selected compounds from Malaria Box: in vitro evaluation, speed of action and drug combination studies |
title | Antiplasmodial profile of selected compounds from Malaria Box: in vitro evaluation, speed of action and drug combination studies |
title_full | Antiplasmodial profile of selected compounds from Malaria Box: in vitro evaluation, speed of action and drug combination studies |
title_fullStr | Antiplasmodial profile of selected compounds from Malaria Box: in vitro evaluation, speed of action and drug combination studies |
title_full_unstemmed | Antiplasmodial profile of selected compounds from Malaria Box: in vitro evaluation, speed of action and drug combination studies |
title_short | Antiplasmodial profile of selected compounds from Malaria Box: in vitro evaluation, speed of action and drug combination studies |
title_sort | antiplasmodial profile of selected compounds from malaria box: in vitro evaluation, speed of action and drug combination studies |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938011/ https://www.ncbi.nlm.nih.gov/pubmed/31888654 http://dx.doi.org/10.1186/s12936-019-3069-3 |
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