Repositioning Salirasib as a new antimalarial agent

Vista sencilla de ítem
dc.citation.titleMedChemCommes
dc.citation.volume10es
dc.creatorPorta, Exequiel Oscar Jesús
dc.creatorBofill Verdaguer, Ignasi
dc.creatorPerez, Consuelo
dc.creatorBanchio, Claudia
dc.creatorFerreira de Azevedo, Mauro
dc.creatorKatzin, Alejandro M.
dc.creatorLabadie, Guillermo Roberto
dc.date.accessioned2020-05-28T13:43:52Z
dc.date.available2020-05-28T13:43:52Z
dc.date.issued2019-06-21
dc.descriptionMalaria 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.es
dc.description.filFil: Porta, Exequiel O. J. Universidad Nacional del Rosario. Facultad de Ciencias Bioquímicas y Farmaceúticas. Instituto de Química Rosario (IQUIR-CONICET); Argentina.es
dc.description.filFil: Bofill Verdaguer, Ignasi. Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitología; Brazil.es
dc.description.filFil: Perez, Consuelo. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.es
dc.description.filFil: Banchio, Claudia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.es
dc.description.filFil: Ferreira de Azevedo, Mauro. Universidade Federal de São Paulo. Departamento de Biociências; Brazil.es
dc.description.filFil: Katzin, Alejandro M. Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitología; Brazil.es
dc.description.filFil: Labadie, Guillermo Roberto. Universidad Nacional del Rosario. Facultad de Ciencias Bioquímicas y Farmaceúticas. Instituto de Química Rosario (IQUIR-CONICET); Argentina.es
dc.description.sponsorshipConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET): PIP 2009-11/0796 and 2012-14/0448es
dc.description.sponsorshipAgencia Nacional de Promoción Científica y Tecnológica (ANPCyT, Argentina): PICT 2011/0589es
dc.description.sponsorshipUniversidad Nacional de Rosario (UNR)es
dc.description.sponsorshipFundación Josefina Pratses
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo: FAPESP 2017/22452-1 and 2015/19316-3es
dc.description.sponsorshipConselho Desenvolvimento Científico e Tecnológico (CNPq, Brasil)es
dc.formatapplication/pdf
dc.format.extent1599-1605es
dc.identifier.issn2040-2503es
dc.identifier.urihttp://hdl.handle.net/2133/18278
dc.language.isoenges
dc.publisherRoyal Society of Chemistryes
dc.relation.publisherversionhttps://doi.org/10.1039/C9MD00298Ges
dc.relation.publisherversionhttps://pubs.rsc.org/en/content/articlelanding/2019/MD/C9MD00298G#!divAbstractes
dc.rightsembargoedAccesses
dc.rights.holderPorta, Exequiel O. J.es
dc.rights.holderBofill Verdaguer, Ignasies
dc.rights.holderPerez, Consueloes
dc.rights.holderBanchio, Claudiaes
dc.rights.holderFerreira de Azevedo, Mauroes
dc.rights.holderKatzin, Alejandro M.es
dc.rights.holderLabadie, Guillermo Robertoes
dc.rights.holderRoyal Society of Chemistryes
dc.rights.holderUniversidad Nacional de Rosario.Facultad de Ciencias Bioquímicas y Farmacéuticases
dc.rights.textAtribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)es
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.es*
dc.subjectMalariaes
dc.subjectDrug repurposinges
dc.subjectClick Chemistryes
dc.subjectPlasmodium falciparumes
dc.subjectSalirasibes
dc.subjectThiosalicylateses
dc.titleRepositioning Salirasib as a new antimalarial agentes
dc.typearticle
dc.typeartículo
dc.typeacceptedVersion
dc.type.collectionarticulo
dc.type.versionacceptedVersiones

Archivos

Bloque original
Mostrando 1 - 1 de 1
Miniatura
Nombre:
sí_53_MedChemComm.pdf
Tamaño:
689.07 KB
Formato:
Adobe Portable Document Format
Descripción:
Versión post-print
Descargar
Bloque de licencias
Mostrando 1 - 1 de 1
Nombre:
license.txt
Tamaño:
3.59 KB
Formato:
Item-specific license agreed upon to submission
Descripción:
Descargar

Colecciones

(FBIOyF) Departamento de Química Orgánica - Artículos