Repositioning Salirasib as a new antimalarial agent

Malaria is a serious tropical disease that kills thousands of people every year, mainly in Africa, due to Plasmodium falciparum infections. Salirasib is a promising cancer drug candidate that interferes with the post-translational modification of Ras. This S-farnesyl thiosalicylate inhibits isopreny...

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Autores principales: Porta, Exequiel Oscar Jesús, Bofill Verdaguer, Ignasi, Perez, Consuelo, Banchio, Claudia, Ferreira de Azevedo, Mauro, Katzin, Alejandro M., Labadie, Guillermo Roberto
Formato: article artículo acceptedVersion
Lenguaje:Inglés
Publicado: Royal Society of Chemistry 2020
Materias:
Malaria
Drug repurposing
Click Chemistry
Plasmodium falciparum
Salirasib
Thiosalicylates
Acceso en línea:http://hdl.handle.net/2133/18278
http://hdl.handle.net/2133/18278
Aporte de:
Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR) de Universidad Nacional de Rosario
id I15-R121-2133-18278
record_format dspace
institution Universidad Nacional de Rosario
institution_str I-15
repository_str R-121
collection Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR)
language Inglés
topic Malaria
Drug repurposing
Click Chemistry
Plasmodium falciparum
Salirasib
Thiosalicylates
spellingShingle Malaria
Drug repurposing
Click Chemistry
Plasmodium falciparum
Salirasib
Thiosalicylates
Porta, Exequiel Oscar Jesús
Bofill Verdaguer, Ignasi
Perez, Consuelo
Banchio, Claudia
Ferreira de Azevedo, Mauro
Katzin, Alejandro M.
Labadie, Guillermo Roberto
Repositioning Salirasib as a new antimalarial agent
topic_facet Malaria
Drug repurposing
Click Chemistry
Plasmodium falciparum
Salirasib
Thiosalicylates
description Malaria is a serious tropical disease that kills thousands of people every year, mainly in Africa, due to Plasmodium falciparum infections. Salirasib is a promising cancer drug candidate that interferes with the post-translational modification of Ras. This S-farnesyl thiosalicylate inhibits isoprenylcysteine carboxyl methyltransferase (ICMT), a validated target for cancer drug development. There is a high homology between the human and the parasite enzyme isoforms, in addition to being a druggable target. Looking to repurpose its structure as an antimalarial drug, a collection of S-substituted derivatives of thiosalicylic acid were prepared by introducing 1,2,3-triazole as a diversity entry point or by direct alkylation of the thiol. We further investigated the in vitro toxicity of FTS analogues to Plasmodium falciparum in the asexual stages and in Vero cells. An antiplasmodial activity assay was performed using a simple, high-sensitivity methodology based on nanoluciferase (NLuc)-transfected P. falciparum parasites. The results showed that some of the analogs were active at low micromolar concentration, including Salirasib. The most potent member of the series has S-farnesyl and the 1,2,3-triazole moiety substituted with phytyl. However, the compound substituted with methyl-naphthyl shows promising physicochemical and activity values. The low cytotoxicity in eukaryotic cells of the most active analogs provided good therapeutic indices, being starting-point candidates for future antimalarial drug development.
format article
artículo
acceptedVersion
author Porta, Exequiel Oscar Jesús
Bofill Verdaguer, Ignasi
Perez, Consuelo
Banchio, Claudia
Ferreira de Azevedo, Mauro
Katzin, Alejandro M.
Labadie, Guillermo Roberto
author_facet Porta, Exequiel Oscar Jesús
Bofill Verdaguer, Ignasi
Perez, Consuelo
Banchio, Claudia
Ferreira de Azevedo, Mauro
Katzin, Alejandro M.
Labadie, Guillermo Roberto
author_sort Porta, Exequiel Oscar Jesús
title Repositioning Salirasib as a new antimalarial agent
title_short Repositioning Salirasib as a new antimalarial agent
title_full Repositioning Salirasib as a new antimalarial agent
title_fullStr Repositioning Salirasib as a new antimalarial agent
title_full_unstemmed Repositioning Salirasib as a new antimalarial agent
title_sort repositioning salirasib as a new antimalarial agent
publisher Royal Society of Chemistry
publishDate 2020
url http://hdl.handle.net/2133/18278
http://hdl.handle.net/2133/18278
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