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A new Cu(I)-chloroquine (CQ) complex [Cu(CQ)(PPh3)2]NO3 (1) was synthesized and characterized, and its mechanism of action studied concomitant with the previously reported complex [Cu(CQ)2]Cl (2). These copper (I) coordination compounds can be considered as potential antimalarial agents because they show better inhibition of the CQ-resistant strain in in vitro studies than CQ alone. In comparison with other metal-CQ complexes, only the gold complex was similar to (1), i.e., more active than CQ against both CQ-susceptible (3D7) and CQ-resistant strains (W2). These two copper (I)-compounds also demonstrated higher antiplasmodial activity against W2 than other copper complexes reported to date. This suggests that the incorporation of the copper metal center enhanced the biological activity of CQ. To better understand their significant growth inhibition of the Plasmodium falciparum parasite, the interaction with two essential molecular targets for the survival and proliferation of the malarial parasite were studied. These were the ferriprotoporphyrin group and the DNA, both important targets for current antimalarial drugs at the asexual erythrocytic stages. Both compounds (1,2) exhibited significant interactions with these targets. In particular, interactions with the DNA were dominated by the intercalator properties of the CQ ligand but may have also been affected by the presence of copper. Overall, these compounds were better parasitic inhibitors than chloroquine diphosphate (CQDP) alone or other previously reported metal-CQ complexes such as platinum, ruthenium and gold. [ABSTRACT FROM AUTHOR]

Half the human population is exposed to malaria. Plasmodium falciparum antimalarial drug resistance monitoring and development of new drugs are major issues related to the control of malaria. Methylene blue (MB), the oldest synthetic antimalarial, is again a promising drug after the break of its use as an antimalarial drug for more than 80 years and a potential partner for triple combination. Very few data are available on the involvement of polymorphisms on genes known to be associated with standard antimalarial drugs and parasite in vitro susceptibility to MB (cross-resistance). In this context, MB susceptibility was evaluated against 482 isolates of imported malaria from Africa by HRP2-based ELISA chemosusceptibility assay. A total of 12 genes involved in antimalarial drug resistance (Pfcrt, Pfdhfr, Pfmdr1, Pfmdr5, Pfmdr6, PfK13, Pfubq, Pfcarl, Pfugt, Pfact, Pfcoronin, and copy number of Pfpm2) were sequenced by Sanger method and quantitative PCR. On the Pfmdr1 gene, the mutation 86Y combined with 184F led to more susceptible isolates to MB (8.0 nM vs. 11.6 nM, p = 0.03). Concerning Pfmdr6, the isolates bearing 12 Asn repetitions were more susceptible to MB (4.6 nM vs. 11.6 nM, p = 0.005). None of the polymorphisms previously described as involved in antimalarial drug resistance was shown to be associated with reduced susceptibility to MB. Some genes (particularly PfK13, Pfugt, Pfact, Pfpm2) did not present enough genetic variability to draw conclusions about their involvement in reduced susceptibility to MB. None of the polymorphisms analyzed by multiple correspondence analysis (MCA) had an impact on the MB susceptibility of the samples successfully included in the analysis. It seems that there is no in vitro cross-resistance between MB and commonly used antimalarial drugs. [ABSTRACT FROM AUTHOR]