Platinum(ii)-chloroquine complexes are antimalarial agents against blood and liver stages by impairing mitochondrial function

dc.creatorMacedo, Taís Soares
dc.creatorVillarreal, Wilmer Jose
dc.creatorCouto, Camila C
dc.creatorMoreira, Diogo Rodrigo de Magalhães
dc.creatorNavarro, Maribel
dc.creatorMachado, Marta
dc.creatorPrudêncio, Miguel
dc.creatorBatista, Alzir Azevedo
dc.creatorSoares, Milena Botelho Pereira
dc.date2018-02-20T16:39:11Z
dc.date2018-02-20T16:39:11Z
dc.date2017
dc.date.accessioned2023-09-27T00:12:47Z
dc.date.available2023-09-27T00:12:47Z
dc.identifierMACEDO, T. S. et al. Platinum(ii)-chloroquine complexes are antimalarial agents against blood and liver stages by impairing mitochondrial function. Metallomics, v. 9, p. 1548-1561, 2017.
dc.identifier0002-9637
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/24889
dc.identifier10.1039/c7mt00196g
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8898568
dc.descriptionFundação de Amparo à Pesquisa do Estado da Bahia (grant PET0042/2013, Brazil), Fundação de Amparo à Pesquisa do Estado de São Paulo (grant 14/10516-7, Brazil) and Fundação para a Ciência e Tecnologia (grant PTDC/SAU-MIC/117060/2010, Portugal).
dc.descriptionChloroquine is an antimalarial agent with strong activity against the blood stage of Plasmodium infection, but with low activity against the parasite's liver stage. In addition, the resistance to chloroquine limits its clinical use. The discovery of new molecules possessing multistage activity and overcoming drug resistance is needed. One possible strategy to achieve this lies in combining antimalarial quinolones with the pharmacological effects of transition metals. We investigated the antimalarial activity of four platinum(ii) complexes composed of chloroquine and phosphine ligands, denoted as WV-90, WV-92, WV-93 and WV-94. In comparison with chloroquine, the complexes were less potent against the chloroquine-sensitive 3D7 strain but they were as active as chloroquine in inhibiting the chloroquine-resistant W2 strain of P. falciparum. Regarding selectivity, the complexes WV-90 and WV-93 displayed higher indexes. Unlike chloroquine, the complexes act as irreversible parasiticidal agents against trophozoites and the WV-93 complex displayed activity against the hepatic stage of P. berghei. The in vivo suppression activity against P. berghei in the Peters 4 day test displayed by the complexes was similar to that of chloroquine. However, the efficacy in an established P. berghei infection in the Thompson test was superior for the WV-93 complex compared to chloroquine. The complexes' antimalarial mechanism of action is initiated by inhibiting the hemozoin formation. While chloroquine efficiently inhibits hemozoin, parasites treated with the platinum complexes display residual hemozoin crystals. This is explained since the interaction of the platinum complexes with ferriprotoporphyrin is weaker than that of chloroquine. However, the complexes caused a loss of mitochondrial integrity and subsequent reduction in mitochondrial activity, and their effects on mitochondria were more pronounced than those in the chloroquine-treated parasites. The dual effect of the platinum complexes may explain their activity against the hemozoin-lacking parasites (hepatic stage), where chloroquine has no activity. Our findings indicate that the platinum(ii)-chloroquine complexes are multifunctional antimalarial compounds and reinforce the importance of metal complexes in antimalarial drug discovery.
dc.formatapplication/pdf
dc.languageeng
dc.publisherRoyal Society of Chemistry
dc.rightsopen access
dc.subjectCloroquina
dc.subjectAntimaláricos
dc.subjectResistência a medicamentos
dc.subjectPlasmodium
dc.subjectPlasmodium Falciparum
dc.subjectChloroquine
dc.subjectAntimalarial
dc.subjectDrug resistance
dc.subjectPlasmodium
dc.subjectPlasmodium Falciparum
dc.titlePlatinum(ii)-chloroquine complexes are antimalarial agents against blood and liver stages by impairing mitochondrial function
dc.typeArticle


Este ítem pertenece a la siguiente institución