Repositioning Salirasib as a new antimalarial agent

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]}

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

• 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
• Modalidade de apoio: 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
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores