Mostrar el registro sencillo del ítem

AutorSouza, Nicolli Bellotti de
AutorCarmo, Arturene Maria Lino
AutorSilva, Adilson David de
AutorFrança, Tanos Celmar Costa
AutorKrettli, Antoniana Ursine
Fecha de acceso2015-03-02T17:23:45Z
Fecha de disponibilización2015-03-02T17:23:45Z
Fecha de publicación2014
ReferenciaSOUZA, Nicolli Bellotti de et al. Antiplasmodial activity of chloroquine analogs against chloroquine-resistant parasites, docking studies and mechanisms of drug action. Malaria Journal, v. 13, p. 469, 2014pt_BR
ISSN1475-2875
URIhttps://www.arca.fiocruz.br/handle/icict/9581
Idiomaengpt_BR
EditorBiomed Central Ltdapt_BR
Derechos de autoropen accesspt_BR
TítuloAntiplasmodial activity of chloroquine analogs against chloroquine-resistant parasites, docking studies and mechanisms of drug actionpt_BR
Tipo del documentoArticlept_BR
DOI10.1186/1475-2875-13-469
Resumen en InglésBackground: Given the threat of resistance of human malaria parasites, including to artemisinin derivatives, new agents are needed. Chloroquine (CQ) has been the most widely used anti-malarial, and new analogs (CQAns) presenting alkynes and side chain variations with high antiplasmodial activity were evaluated. Methods: Six diaminealkyne and diaminedialkyne CQAns were evaluated against CQ-resistant (CQ-R) (W2) and CQ-sensitive (CQ-S) (3D7) Plasmodium falciparum parasites in culture. Drug cytotoxicity to a human hepatoma cell line (HepG2) evaluated, allowed to calculate the drug selectivity index (SI), a ratio of drug toxicity to activity in vitro. The CQAns were re-evaluated against CQ-resistant and -sensitive P. berghei parasites in mice using the suppressive test. Docking studies with the CQAns and the human (HssLDH) or plasmodial lactate dehydrogenase (PfLDH) enzymes, and, a β-haematin formation assay were performed using a lipid as a catalyst to promote crystallization in vitro. Results: All tested CQAns were highly active against CQ-R P. falciparum parasites, exhibiting half-maximal inhibitory concentration (IC50) values below 1 μΜ. CQAn33 and CQAn37 had the highest SIs. Docking studies revealed the best conformation of CQAn33 inside the binding pocket of PfLDH; specificity between the residues involved in H-bonds of the PfLDH with CQAn37. CQAn33 and CQAn37 were also shown to be weak inhibitors of PfLDH. CQAn33 and CQAn37 inhibited β-haematin formation with either a similar or a 2-fold higher IC50 value, respectively, compared with CQ. CQAn37 was active in mice with P. berghei, reducing parasitaemia by 100%. CQAn33, -39 and -45 also inhibited CQ-resistant P. berghei parasites in mice, whereas high doses of CQ were inactive. Conclusions: The presence of an alkyne group and the size of the side chain affected anti-P. falciparum activityin vitro. Docking studies suggested a mechanism of action other than PfLDH inhibition. The β-haematin assay suggested the presence of an additional mechanism of action of CQAn33 and CQAn37. Tests with CQAn34, CQAn37, CQAn39 and CQAn45 confirmed previous results against P. berghei malaria in mice, and CQAn33, 39 and 45 were active against CQ-resistant parasites, but CQAn28 and CQAn34 were not. The result likely reflects structure-activity relationships related to the resistant phenotype.pt_BR
AfiliaciónFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, Brazilpt_BR
AfiliaciónUniversidade Federal de Juiz de Fora. Instituto de Ciências Exatas. Departamento de Química. Juiz de Fora, MG, Brazilpt_BR
AfiliaciónUniversidade Federal de Juiz de Fora. Instituto de Ciências Exatas. Departamento de Química. Juiz de Fora, MG, Brazilpt_BR
AfiliaciónInstituto Militar de Engenharia. Laboratório de Modelagem Molecular Aplicada à Defesa Química e Biológica. Rio de Janeiro, RJ, Brazilpt_BR
AfiliaciónFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, Brazilpt_BR
Palavras clave en InglêsMalariapt_BR
Palavras clave en InglêsChloroquine analogspt_BR
Palavras clave en InglêsDiaminealkynept_BR
Palavras clave en InglêsP. falciparumpt_BR
Palavras clave en InglêsLactate-dehydrogenase enzymept_BR
Palavras clave en InglêsDockingpt_BR


Ficheros en el ítem

application/pdf
Nombre:
2014_121.pdf
Tamaño:
1.214Mb
Formato:
application/
Ver/Abrir

Este ítem aparece en la(s) siguiente(s) colección(ones)

Mostrar el registro sencillo del ítem