Repositioning salirasib as new antimalarial agent

PORTA, EXEQUIEL OSCAR JESÚS; BOFILL VERDAGUER, IGNASI; PÉREZ, CONSUELO; BANCHIO, CLAUDIA; FERREIRA DE AZEVEDO, MAURO; KATZIN, ALEJANDRO; LABADIE, GUILLERMO R

MedChemComm

Royal Chemical Society

Lugar: Londres; Año: 2019

2040-2503

Malaria is a neglected 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 thiosalycylate inhibits the isoprenyl carboxyl methyltransferase (ICMT), being a validated target for cancer drug development. Looking to repurpose its structure as antimalarial drug, a collection of S-substituted derivatives of thiosalicylic acid were prepared, introducing a 1,2,3-triazol as 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. The 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. The most potent member of the series has S-farnesyl and the 1,2,3-triazole moiety substituted with methyl-naphtyl. The low cytotoxicity in eukaryotic cells of the most active analogs provided good therapeutic indexes, being promising candidates for future antimalarial drugs development.