Molecular and Biological Aspects of Antimalarial Resistance in Plasmodium falciparum and Plasmodium vivax

Bustamante, Carolina; Batista, Camila N.; Zalis, Mariano Gustavo

doi:10.2174/138945009787581131

Cited by 8 publications

(6 citation statements)

References 131 publications

(185 reference statements)

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“…This suggests these complexes use a different action mechanism than quinoline-based antimalarial drugs. In view of the current problem of resistance to anti-malarial drugs, 3 it is especially important to identify novel anti-malarial drug candidates not based on quinolines.…”

Section: Advanced Biological Experimentsmentioning

confidence: 99%

“…1 However, it is estimated that this death rate is likely to increase further because of the high level of drug resistance to most of the clinically used antimalarials. 2 Given the evidence of the global spread of drug resistance, 3 there is a need for the identification of new antiplasmodial drugs. After malaria, amebiasis (caused by Entamoeba histolytica) is the second leading cause of death from a protozoan parasite.…”

Section: Introductionmentioning

confidence: 99%

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Structure–activity relationships of mononuclear metal–thiosemicarbazone complexes endowed with potent antiplasmodial and antiamoebic activities

Bahl

Athar

Soares

et al. 2010

Bioorganic & Medicinal Chemistry

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A useful concept for the rational design of antiparasitic drug candidates is the complexation of bioactive ligands with transition metals. In view of this, an investigation was conducted into a new set of metal complexes as potential antiplasmodium and antiamoebic agents, in order to examine the importance of metallic atoms, as well as the kind of sphere of co-ordination, in these biological properties. Four functionalized furyl-thiosemicarbazones (NT1-4) treated with divalent metals (Cu, Co, Pt, and Pd) to form the mononuclear metallic complexes of formula [M(L)2Cl2] or [M(L)Cl2] were examined. The pharmacological characterization, including assays against Plasmodium falciparum and Entamoeba histolytica, cytotoxicity to mammalian cells, and interaction with pBR 322 plasmid DNA was performed. Structure-activity relationship data revealed that the metallic complexation plays an essential role in antiprotozoal activity, rather than the simple presence of the ligand or metal alone. Important steps towards identification of novel antiplasmodium (NT1Cu, IC50 of 4.6 microM) and antiamoebic (NT2Pd, IC50 of 0.6 microM) drug prototypes were achieved. Of particular relevance to this work, these prototypes were able to reduce the proliferation of these parasites at concentrations that are not cytotoxic to mammalian cells.

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Section: Advanced Biological Experimentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure–activity relationships of mononuclear metal–thiosemicarbazone complexes endowed with potent antiplasmodial and antiamoebic activities

Bahl

Athar

Soares

et al. 2010

Bioorganic & Medicinal Chemistry

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“…Although the disease is curable if the infected individuals are treated rapidly and properly, the parasite rapidly develops resistance to common antimalarial drugs, such as chloroquine (21,22). To overcome the resistance, combination therapy was introduced in clinical experiments; for example, the combination of sulfadoxin and pyrimethamine has been regarded as an effective method for the treatment of malaria, but is becoming less efficacious (21,22). Artemisinin, derived from the plant Artemisia annua , is known to be an extremely effective anti-malarial drug and has been used in first-line treatment for the past few years.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics simulations of PfAQP from the malarial parasite Plasmodium falciparum

Cui

Bastien

2012

Mol Med Report

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Aquaporins (AQPs) are widely distributed in all kingdoms of life and act as facilitators in the transport of water and other small solutes through cell membranes. Since the plasmodial and human AQPs are different in their primary and secondary structure, an intervention targeting plasmodial AQP without affecting human AQPs is discussed to identify an attractive novel target against malaria. Therefore, it is crucial to understand the action mechanisms of these plasmodial AQPs. To explore the progression of the plasmodial real AQPs in vivo at work, a molecular dynamic simulation system was successfully developed for a PfAQP tetramer in silico. The results showed that the transporting work was not synchronous in the four channels at the same time, and that it was different at different times in the same channel. The hole sizes varied in different channels with time. The structure analysis showed that both hydrophobic and hydrophilic residues composed the inner surface of the channels, and the asparagines Asn-193 and Asn-70 assembled into two motifs of NLA and NPS in the center of the channel in place of the signature motifs of NPA in other AQPs. In brief, we successfully developed an equilibrated PfAQP-lipid system by molecular dynamics simulations, and investigated the structure of the PfAQP channel, which should aid our understanding of the AQP structure and its functional implications.

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“…Development of drug resistance, particularly in Plasmodium, is a major threat for human health and stock breeding, thus motivating the development of novel drug therapies (3,7). The mitochondrial physiology of apicomplexan parasites differs in several aspects from the physiology of mammalian mitochondria (10,15).…”

Section: -Hydroxy-2-dodecyl-4(1h)quinolone (Hdq) Was Recently Identimentioning

confidence: 99%

In Vitro and In Vivo Activities of 1-Hydroxy-2-Alkyl-4(1 H )Quinolone Derivatives against Toxoplasma gondii

Bajohr

Platte

et al. 2010

Antimicrob Agents Chemother

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1-Hydroxy-2-dodecyl-4(1H)quinolone (HDQ) was recently identified as a Toxoplasma gondii inhibitor.We describe here two novel 1-hydroxyquinolones, which displayed 50% inhibitory concentrations 10-and 5-fold lower than that of HDQ. In a mouse model of acute toxoplasmosis, these two compounds and HDQ reduced the percentages of infected peritoneal cells and decreased the parasite loads in lungs and livers. Compound B showed a tendency toward lowering parasite loads in brains in a mouse model of toxoplasmic encephalitis.Apicomplexan parasites are widespread human pathogens causing diseases such as malaria and toxoplasmosis. Development of drug resistance, particularly in Plasmodium, is a major threat for human health and stock breeding, thus motivating the development of novel drug therapies (3, 7). The mitochondrial physiology of apicomplexan parasites differs in several aspects from the physiology of mammalian mitochondria (10,15). This feature can be exploited for drug therapy, as shown by treatment with the complex III inhibitor atovaquone (1, 2, 12, 16). 1-Hydroxy-2-dodecyl-4(1H)quinolone (HDQ) was recently shown to effectively inhibit parasite replication of Toxoplasma gondii and Plasmodium falciparum in tissue culture (13). The structural similarity of HDQ and coenzyme Q (6) suggests an inhibition of ubiquinol binding enzymes as a mode of action. Using inhibition kinetics on heterologously expressed enzymes, we recently demonstrated that HDQ is a high-affinity inhibitor of the T. gondii alternative NADH dehydrogenase (TgNDH2-I) (9). HDQ treatment in T. gondii results in a rapid loss of the mitochondrial membrane potential and a subsequent reduction of the cellular ATP concentration (8). HDQ was reported to inhibit the parasitic dihydroorotate dehydrogenase (DHODH) in P. falciparum (4), thus inhibiting the fourth step of the essential de novo pyrimidine synthesis, which uses ubiquinol reduction as an electron sink for dihydroorotate oxidation.Based on the structure of HDQ, we here describe four novel 1-hydroxyquinolones (compounds A to D) and their anti-Toxoplasma activities and provide the first data on the in vivo efficacy of HDQ, as well as those of compounds A and B, in a mouse model of acute toxoplasmosis. We had previously shown that a long alkyl side chain at C-2 in HDQ of more than five carbons is critical for the anti-Toxoplasma activities of 1-hydroxy-2-alkyl-4(1H)quinolones (13), and it was thus of interest to investigate whether its location at C-2 is strictly required for the antiparasitic effect. In addition, from previous investigations, it was not clear whether the hydrogen at C-3 in HDQ is needed. We therefore prepared the two new 1-hydroxyquinolones, compounds A and B (L. F. Tietze et al., unpublished data). In compound A, the hydrogen at C-3 in HDQ is replaced by a methyl group, and in compound B, the dodecyl and the methyl moiety were swapped (Fig. 1). Furthermore, we synthesized two HDQ derivatives, compounds C and D, containing a N,N-dimethylaminoethoxy group at C-6, in order to improve th...

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Molecular and Biological Aspects of Antimalarial Resistance in Plasmodium falciparum and Plasmodium vivax

Cited by 8 publications

References 131 publications

Structure–activity relationships of mononuclear metal–thiosemicarbazone complexes endowed with potent antiplasmodial and antiamoebic activities

Structure–activity relationships of mononuclear metal–thiosemicarbazone complexes endowed with potent antiplasmodial and antiamoebic activities

Molecular dynamics simulations of PfAQP from the malarial parasite Plasmodium falciparum

In Vitro and In Vivo Activities of 1-Hydroxy-2-Alkyl-4(1 H )Quinolone Derivatives against Toxoplasma gondii

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