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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Repositioning Salirasib as a new antimalarial agent

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Autor(es):
Porta, Exequiel O. J. [1] ; Verdaguer, Ignasi Bofill [2] ; Perez, Consuelo [3] ; Banchio, Claudia [3] ; Ferreira de Azevedo, Mauro [4] ; Katzin, Alejandro M. [2] ; Labadie, Guillermo R. [1, 5]
Número total de Autores: 7
Afiliação do(s) autor(es):
[1] UNR, CONICET, Inst Quim Rosario, Suipacha 531, S2002LRK, Rosario, Santa Fe - Argentina
[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, Sao Paulo - Brazil
[3] Univ Nacl Rosario, Fac Ciencias Bioquim & Farmaceut, Inst Biol Mol & Celular IBR CONICET UNR, Suipacha 531, S2002LRK, Rosario, Santa Fe - Argentina
[4] Univ Fed Sao Paulo, Dept Biociencias, Santos - Brazil
[5] Univ Nacl Rosario, Fac Ciencias Bioquim & Farmaceut, Dept Quim Organ, Suipacha 531, S2002LRK, Rosario, Santa Fe - Argentina
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: MedChemComm; v. 10, n. 9, p. 1599-1605, SEP 1 2019.
Citações Web of Science: 0
Resumo

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. (AU)

Processo FAPESP: 17/22452-1 - Biossíntese de isoprenóides em Plasmodium falciparum: avaliação de possíveis alvos para a obtenção de novas drogas antimaláricas
Beneficiário:Alejandro Miguel Katzin
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 15/19316-3 - Mecanismos de egresso em P. falciparum: identificação de novos alvos terapêuticos
Beneficiário:Mauro Ferreira de Azevedo
Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores