Chloroquine-containing organoruthenium complexes are fast-acting multistage antimalarial agents

Abstract

We report the pharmacological activity of organoruthenium complexes containing chloroquine (CQ) as a chelating ligand. The complexes displayed intraerythrocytic activity against CQ-sensitive 3D7 and CQ-resistant W2 strains of Plasmodium falciparum, with potency and selectivity indexes similar to those of CQ. Complexes displayed activity against all intraerythrocytic stages, but moderate activity against Plasmodium berghei liver stages. However, unlike CQ, organoruthenium complexes impaired gametocyte viability and exhibited fast parasiticidal activity against trophozoites for P. falciparum. This functional property results from the ability of complexes to quickly induce oxidative stress. The parasitaemia of P. berghei-infected mice was reduced by treatment with the complex. Our findings demonstrated that using chloroquine for the synthesis of organoruthenium complexes retains potency and selectivity while leading to an increase in the spectrum of action and parasite killing rate relative to CQ.

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

“…The previously reported antimalarial organoruthenium-chloroquine complexes inhibited b-hematin formation and induced ROS which was even more pronounced than chloroquine. 21 Collectively, these findings suggest that the nature of the transition metal can play an important role in the pharmacological profile of chloroquine-metal complexes, which is a common feature observed in the literature. [29][30][31] We observed by electron microscopy that the platinum complex-treated parasites exhibited loss of mitochondrial material.…”

“…These organoruthenium complexes affected trophozoites by inhibiting hemozoin formation and producing reactive oxygen species (ROS) but, unlike chloroquine, they exhibited fast parasiticidal activity against blood stages and reduced viability of gametocytes. 21 To advance the knowledge of antiparasitic metal complexes, we now examined in great detail a class of recently discovered platinum(II) complexes containing chloroquine and phosphine ligands in their composition.…”

Targeting of the mitochondrion by dinuclear thiolato-bridged arene ruthenium complexes in cancer cells and in the apicomplexan parasite Neospora caninum

“…Organometallic ruthenium-arene complexes have risen to prominence as a pharmacophore due to the success of other ruthenium drug candidates in clinical trials. 51 Substantial activities of arene ruthenium complexes have been reported in infectious diseases caused by bacteria 52,53 against protozoan parasites including T. gondii 29,30 and Plasmodium falciparum, 54,55 and against helminths such as Schistosoma mansoni 56,57 and Echinococcus multilocularis. 28 In addition, a series of ruthenium-clotrimazole (ctz) complexes displayed high and specific in vitro activity against Leishmania major and Trypanosoma cruzi.…”

A Novel Hybrid of Chloroquine and Primaquine Linked by Gold(I): Multitarget and Multiphase Antiplasmodial Agent

“…The solid was dried and infrared spectra were obtained with KBr pallets. Primaquine and chloroquine were used as negative and positive controls, respectively [67] …”