The mechanism of antimalarial action of the ruthenium(II)–chloroquine complex [RuCl2(CQ)]2

Abstract

The mechanism of antimalarial action of the ruthenium-chloroquine complex [RuCl 2 (CQ)] 2 (1), previously shown by us to be active in vitro against CQ-resistant strains of Plasmodium falciparum and in vivo against P. berghei, has been investigated. The complex is rapidly hydrolyzed in aqueous solution to [RuCl(OH 2 ) 3 (CQ)] 2 [Cl] 2 , which is probably the active species. This compound binds to hematin in solution and inhibits aggregation to β-hematin at pH ∼ 5 to a slightly lower extent than chloroquine diphosphate; more importantly, the heme aggregation inhibition activity of complex 1 is significantly higher than that of CQ when measured at the interface of noctanol-aqueous acetate buffer mixtures under acidic conditions modeling the food vacuole of the parasite. Partition coefficient measurements confirmed that complex 1 is considerably more lipophilic than CQ in n-octanol-water mixtures at pH ∼ 5. This suggests that the principal target of complex 1 is the heme aggregation process, which has recently been reported to be fast and spontaneous at or near water-lipid interfaces. The enhanced antimalarial activity of complex 1 is thus probably due to a higher effective concentration of the drug at or near the interface compared with that of CQ, which accumulates strongly in the aqueous regions of the vacuole under those conditions. Furthermore, the activity of complex 1 against CQ-resistant strains of P. falciparum is probably related to its greater lipophilicity, in line with previous reports indicating a lowered ability of the mutated transmembrane transporter PfCRT to promote the efflux of highly lipophilic drugs. The metal complex also interacts with DNA by intercalation, to a comparable extent and in a similar manner to uncomplexed CQ and therefore DNA binding does not appear to be an important part of the mechanism of antimalarial action in this case.

Cytotoxicity of Ru(II) piano–stool complexes with chloroquine and chelating ligands against breast and lung tumor cells: Interactions with DNA and BSA

“…Overall, complexes 1-5 present low hypochromism and also low Kb 1 and Kb 2 values compared with their analogous with CQ, and the overall positive charge could offer an interacts electrostatics with the phosphate groups. The constants exhibited by complexes 6, 7, 8 and 9 were similar to those found for free CQ, and the same order of magnitude for analogous ruthenium-CQ and platinum-CQ complexes [43].…”

Gold complexes as potential anti-parasitic agents

“…Also, this complex inhibited the ␤-hematin (synthetic haemozoin) formation at comparable concentration to CQ [44]. The evaluation of this complex on the haeme aggregation inhibition in the water-lipid interface is in progress [50].…”

Synthesis, characterization, DNA interaction studies and anticancer activity of platinum–clotrimazole complexes

“…The absorbance of the ctDNA solution (70 lM) was monitored at 260 nm before and after incubation with the drug (15 lM in Tris/HCl buffer) for 1 h at room temperature. The temperature was increased by 1°C/min between 55 and 70°C and by 3°C/min between 40 and 55°C and between 70 and 95°C [32].…”