pyrimidinones and Malaria

Heat shock proteins act as molecular chaperones, facilitating protein folding in cells of living organisms. Their role is particularly important in parasites because environmental changes associated with their life cycles place a strain on protein homoeostasis. Not surprisingly, some heat shock proteins are essential for the survival of the most virulent malaria parasite, Plasmodium falciparum. This justifies the need for a greater understanding of the specific roles and regulation of malarial heat shock proteins. Furthermore, heat shock proteins play a major role during invasion of the host by the parasite and mediate in malaria pathogenesis. The identification and development of inhibitor compounds of heat shock proteins has recently attracted attention. This is important, given the fact that traditional antimalarial drugs are increasingly failing, as a consequence of parasite increasing drug resistance. Heat shock protein 90 (Hsp90), Hsp70/Hsp40 partnerships and small heat shock proteins are major malaria drug targets. This review examines the structural and functional features of these proteins that render them ideal drug targets and the challenges of targeting these proteins towards malaria drug design. The major antimalarial compounds that have been used to inhibit heat shock proteins include the antibiotic, geldanamycin, deoxyspergualin and pyrimidinones. The proposed mechanisms of action of these molecules and the pathways they inhibit are discussed.

Topics: Animals; Antimalarials; Benzoquinones; Guanidines; Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Malaria; Parasitic Sensitivity Tests; Plasmodium; Pyrimidinones; Structure-Activity Relationship

The genetic deficiency of human PNP causes a specific immunodeficiency by inducing apoptosis in dividing T-cells. Powerful inhibitors of PNP have been designed from the experimental determination of the transition state structure of PNPs. The Immucillins are transition state analogue inhibitors with Kd values as low as 7 pM. In the presence of deoxyguanosine the Immucillins kill activated human T-cells but not other cell types. The Immucillins are orally available and of low toxicity to mice. Immucillins also inhibit PNP from Plasmodium falciparum. Parasites cultured in human erythrocytes are killed by purine starvation in the presence of Immucillins and can be rescued by hypoxanthine.

Topics: Animals; Anti-Bacterial Agents; Cell Proliferation; Deoxyguanosine; Erythrocytes; Humans; Hypoxanthine; Kinetics; Lymphocyte Activation; Malaria; Models, Chemical; Phenotype; Plasmodium falciparum; Purine Nucleosides; Purines; Pyrimidinones; Pyrroles; T-Lymphocytes

Alteration of insect growth regulators by the action of inhibitors is becoming an attractive strategy to combat disease-transmitting insects. In the present study, we investigated the larvicidal effect of 1,2,3-triazolyl-pyrimidinone derivatives against the larvae of the mosquito

Topics: Animals; Anopheles; Carrier Proteins; Insecticides; Juvenile Hormones; Larva; Malaria; Molecular Docking Simulation; Mosquito Control; Mosquito Vectors; Pyrimidinones

Topics: Adenine; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cote d'Ivoire; Cyclopropanes; Drug Therapy, Combination; Enterobacter aerogenes; Enterobacteriaceae Infections; Fanconi Syndrome; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Malaria; Male; Middle Aged; Organophosphonates; Pyelonephritis; Pyrimidinones; Ritonavir; Tenofovir

Recent studies have demonstrated that human immunodeficiency virus (HIV) protease inhibitors (PIs) exert inhibitory effects on erythrocytic stages of the human-malaria parasite Plasmodium falciparum in vitro and on erythrocytic stages of the rodent-malaria parasite Plasmodium chabaudi in vivo. Although it remains unclear how HIV PIs inhibit the parasite, the effect seen on parasite development in the erythrocytic stages is potent. The effect on preerythrocytic stages has not yet been investigated. Using the rodent parasite Plasmodium berghei, we screened a panel of HIV PIs in vitro for effects on the preerythrocytic stages. Our data indicated that the HIV PIs lopinavir and saquinavir affect preerythrocytic-stage parasite development in vitro. We then evaluated the effect of HIV PIs on preerythrocytic stages in vivo using the rodent parasite Plasmodium yoelii. We found that lopinavir/ritonavir had a dose-dependent effect on liver-stage parasite development. Given that sub-Saharan Africa is where the HIV/AIDS pandemic intersects with malaria, these results merit analysis in clinical settings.

Topics: Animals; Anopheles; Female; HIV Infections; HIV Protease Inhibitors; Lopinavir; Malaria; Mice; Plasmodium; Plasmodium berghei; Plasmodium yoelii; Pyrimidinones; Ritonavir

The synergy of the activities between chloroquine and various human immunodeficiency virus protease inhibitors was investigated in chloroquine-resistant and -sensitive malaria parasites. In both in vitro and in vivo assay systems, ritonavir was found to be the most potent in potentiating the antimalarial action of chloroquine.

Topics: Animals; Antimalarials; Atazanavir Sulfate; Chloroquine; Drug Resistance; Drug Synergism; Female; HIV Protease Inhibitors; Humans; In Vitro Techniques; Lopinavir; Malaria; Mice; Nelfinavir; Oligopeptides; Plasmodium chabaudi; Plasmodium falciparum; Pyridines; Pyrimidinones; Ritonavir; Saquinavir

Febrifugine (1), a quinazoline alkaloid, isolated from Dichroa febrifuga roots, shows powerful antimalarial activity against Plasmodium falciparum. The use of 1 as an antimalarial drug has been precluded because of side effects, such as diarrhea, vomiting, and liver toxicity. However, the potent antimalarial activity of 1 has stimulated medicinal chemists to pursue compounds derived from 1, which may be valuable leads for novel drugs. In this study, we synthesized a new series of febrifugine derivatives formed by structural modifications at (i) the quinazoline ring, (ii) the linker, or (iii) the piperidine ring. Then, we evaluated their antimalarial activities. Thienopyrimidine analogue 15 exhibited a potent antimalarial activity and a high therapeutic selectivity both in vitro and in vivo, suggesting that 15 is a good antimalarial candidate.

Topics: Animals; Antimalarials; Cell Line; Malaria; Mice; Parasitic Sensitivity Tests; Piperidines; Plasmodium berghei; Plasmodium falciparum; Pyrimidinones; Quinazolines; Stereoisomerism; Structure-Activity Relationship; Thiophenes; Toxicity Tests, Acute

The photosensitizing dye merocyanine 540 (MC 540) was evaluated as a means for purging malarially infected red cells from murine blood using the rodent malarial pathogens, Plasmodium yoelii and Plasmodium berghei, as models of human malaria. Malarially infected red cells bound more MC 540 and were more sensitive to MC 540-sensitized photoirradiation than were noninfected erythroid cells. Extracorporeal exposure of infected red cells to the dye and white light prevented the transmission of the disease in a transfusion model. P. berghei-infected red cells were more resistant to the antimalarial activity of MC 540 than were P. yoelii-infected cells, presumably because P. berghei preferentially infects reticulocytes whereas P. yoelii infects mature red cells. The possibility of using photoirradiation sensitized by MC 540 or related dyes to purge malarially infected donor blood is discussed.

Topics: Animals; Blood Transfusion; Disease Models, Animal; Erythrocytes; Female; Flow Cytometry; Malaria; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Microscopy, Fluorescence; Photochemotherapy; Plasmodium; Plasmodium berghei; Plasmodium yoelii; Pyrimidinones; Radiation-Sensitizing Agents

Lymphoid and liver damage does not usually occur in Plasmodium vinckei-infected mice until parasitaemias reach 70-80 per cent and the mice are showing signs of illness. We report here that these changes can be induced in mice of healthy appearance and lower parasitaemia by injecting divicine or tertiary-butyl hydroperoxide, two generators of free oxygen radicals. The same or larger doses of these radical generators did not induce this tissue damage in normal mice. Phagocytic leukocytes are activated in P. vinckei-infected mice, and secretion by these cells of toxic oxygen metabolites has been suggested to be part of this process. Additive effects of these free radicals and those generated from divicine and t-butyl hydroperoxide could account for the increased susceptibility of parasitized mice to tissue damage by these agents.

Topics: Animals; Female; Liver; Lymphoid Tissue; Malaria; Male; Mice; Peroxides; Plasmodium; Pyrimidinones; tert-Butylhydroperoxide

Intravenous injection of divicine into mice infected with Plasmodium vinckei rapidly killed the parasites and caused haemolysis. Degenerating parasites were observed frequently inside intact circulating erythrocytes, implying that parasite death was not a passive consequence of haemolysis. Both parasite death and haemolysis were prevented by the iron chelator desferrioxamine. In vitro, divicine caused the accumulation of malonyldialdehyde and the depletion of reduced glutathione in normal mouse erythrocytes. Desferrioxamine inhibited the former event, but not the latter. These observations support the hypothesis advanced by Huheey & Martin (Experientia, 31, 1145, 1975) to explain the patchy geographical distribution of glucose-6-phosphate dehydrogenase deficiency in historic malarial areas and also suggest that desferrioxamine, a drug already in clinical use, is a potential treatment for favism and other examples of oxidative haemolysis.

Topics: Animals; Deferoxamine; Erythrocytes; Favism; Female; Glucosephosphate Dehydrogenase Deficiency; Glutathione; Hemolysis; Malaria; Male; Malondialdehyde; Mice; Mice, Inbred CBA; Microscopy, Electron; Pyrimidinones

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Bacillus subtilis; Candida albicans; Enterococcus faecalis; Escherichia coli; Malaria; Mice; Microbial Sensitivity Tests; Plasmodium berghei; Proteus vulgaris; Pseudomonas aeruginosa; Purinones; Pyrimidinones; Schistosoma mansoni; Staphylococcus; Thiadiazoles; Trypanosoma cruzi