Synthesis and antimalarial activity in vitro of new heterobimetallic complexes: Rh and Au derivatives of chloroquine and a series of ferrocenyl-4-amino-7-chloroquinolines

Blackie, Margaret A.L.; Beagley, Paul; Chibale, Kelly; Clarkson, Cailean; Moss, John R.; Smith, Peter J.

doi:10.1016/j.jorganchem.2003.07.026

Cited by 46 publications

(31 citation statements)

References 16 publications

(14 reference statements)

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“…In previous publications [16,39], we have demonstrated that binding CQ to gold in the complex [Au(CQ)(PPh 3 )]PF 6 ( 1 ) and other related compounds [40], results in an enhancement of the in vitro potency against CQ-resistant strains of P. falciparum and a high in vivo activity against P. berghei (rodent malaria) without any evidence for acute toxic effects even after prolonged treatment. Similarly, Ru-CQ complexes [41], and notably ferroquine [42] have been shown to be active against resistant malaria parasites and they seem to retain heme aggregation inhibition as the principal mechanism of action.…”

Section: Resultsmentioning

confidence: 99%

The mechanism of antimalarial action of [Au(CQ)(PPh3)]PF6: Structural effects and increased drug lipophilicity enhance heme aggregation inhibition at lipid/water interfaces

Navarro

Castro

Martínez

et al. 2011

Journal of Inorganic Biochemistry

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The mechanism of antimalarial action of [Au(CQ)(PPh 3 )] PF 6 (1), which is active in vitro against CQ-resistant P. falciparum and in vivo against P. berghei, has been investigated in relation to hemozoin formation and DNA as possible important targets. Complex 1 interacts with heme and inhibits β-hematin formation both in aqueous medium and near water/n-octanol interfaces at pH 5 to a greater extent than chloroquine diphosphate (CQDP) or other known metal-based antimalarial agents; the higher inhibition activity is probably related to the higher lipophilicity observed for 1 through partition coefficient measurements at low pH, with respect to CQDP. The interactions of complex 1 with DNA were explored using spectrophotometric and fluorimetric titrations, circular dichroism spectroscopy, viscosity and melting point studies, as well as electrophoresis and covalent binding assays. The experimental data indicate that complex 1 interacts with DNA predominantly by intercalation and electrostatic association of the CQ moiety, similarly to free CQDP, while no covalent metal-DNA binding seems to take place. The most likely antimalarial mechanism for complex 1 is thus heme aggregation inhibition; the high activities observed against resistant parasites are probably due to the structural modification of CQ introduced by the presence of the gold-triphenylphosphine fragment, together with the enhanced lipophilic character.

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Section: Resultsmentioning

confidence: 99%

The mechanism of antimalarial action of [Au(CQ)(PPh3)]PF6: Structural effects and increased drug lipophilicity enhance heme aggregation inhibition at lipid/water interfaces

Navarro

Castro

Martínez

et al. 2011

Journal of Inorganic Biochemistry

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show abstract

“…However, it is noteworthy that complex 8 showed comparable antiplasmodial activity to the falcipain-2 inhibitor E64. Blackie et al [37] showed that while ferrocenyl 4-aminoquinolines displayed improved efficacy with respect to CQ, complexation of the second metal to ferrocenyl 4-aminoquinolines proved unimportant to the overall efficacy.…”

Section: In Vitro Antiplasmodial Activitymentioning

confidence: 99%

Synthesis and in vitro evaluation of gold(I) thiosemicarbazone complexes for antimalarial activity

Khanye

Smith

Lategan

et al. 2010

Journal of Inorganic Biochemistry

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“…As a matter of fact, gold-containing drugs have previously been shown to be toxic for Plasmodia [45-57]. Drugs could specifically enter infected erythrocytes, as the pathogen dramatically enhances the permeability of the erythrocyte membrane [1].…”

Section: Resultsmentioning

confidence: 99%

Beneficial effect of aurothiomalate on murine malaria

Alesutan

Bobbala

Qadri

et al. 2010

Malar J

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BackgroundPremature death of Plasmodium-infected erythrocytes is considered to favourably influence the clinical course of malaria. Aurothiomalate has previously been shown to trigger erythrocyte death or eryptosis, which is characterized by cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. Phosphatidylserine-exposing cells are rapidly cleared from circulating blood. The present study thus tested whether sodium aurothiomalate influences the intraerythrocytic parasite development in vitro and the clinical course of murine malaria in vivo.MethodsHuman erythrocytes were infected with Plasmodium falciparum BinH in vitro and mice were infected (intraperitoneal injection of 1 × 106 parasitized murine erythrocytes) with Plasmodium berghei ANKA in vivo.ResultsExposure to aurothiomalate significantly decreased the in vitro parasitemia of P. falciparum-infected human erythrocytes without influencing the intraerythrocytic DNA/RNA content. Administration of sodium aurothiomalate in vivo (daily 10 mg/kg b.w. s.c. from the 8th day of infection) enhanced the percentage of phosphatidylserine-exposing infected and noninfected erythrocytes in blood. All nontreated mice died within 30 days of infection. Aurothiomalate-treatment delayed the lethal course of malaria leading to survival of more than 50% of the mice 30 days after infection.ConclusionsSodium aurothiomalate influences the survival of Plasmodium berghei-infected mice, an effect only partially explained by stimulation of eryptosis.

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Synthesis and antimalarial activity in vitro of new heterobimetallic complexes: Rh and Au derivatives of chloroquine and a series of ferrocenyl-4-amino-7-chloroquinolines

Cited by 46 publications

References 16 publications

The mechanism of antimalarial action of [Au(CQ)(PPh3)]PF6: Structural effects and increased drug lipophilicity enhance heme aggregation inhibition at lipid/water interfaces

The mechanism of antimalarial action of [Au(CQ)(PPh3)]PF6: Structural effects and increased drug lipophilicity enhance heme aggregation inhibition at lipid/water interfaces

Synthesis and in vitro evaluation of gold(I) thiosemicarbazone complexes for antimalarial activity

Beneficial effect of aurothiomalate on murine malaria

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