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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Repositioning Salirasib as a new antimalarial agent

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Author(s):
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]
Total Authors: 7
Affiliation:
[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
Total Affiliations: 5
Document type: Journal article
Source: MedChemComm; v. 10, n. 9, p. 1599-1605, SEP 1 2019.
Web of Science Citations: 0
Abstract

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)

FAPESP's process: 17/22452-1 - Biosynthesis of isoprenoids in Plasmodium falciparum: evaluation of possible targets to obtain new anti-malarial drugs
Grantee:Alejandro Miguel Katzin
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 15/19316-3 - Regulation of P. falciparum egress from the host cell: identification of new targets
Grantee:Mauro Ferreira de Azevedo
Support Opportunities: Research Grants - Young Investigators Grants