Antimalarial activity of tetrahydrohomopteroic acid.
Tetrahydrohomopteroic acid, an analog of tetrahydrofolic acid, shows antimalarial activity against Plasmodium cynomolgi and a pyrimethamine-resistant variant of this organism.
Animals↗
SEARCH · Search PubMed
Results for “Antimalarials”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Antimalarials: effects on in vivo and in vitro protein synthesis.
The antimalarials quinine, chloroquine, primaquine, and quinacrine inhibited the uptake and incorporation of amino acids in vivo, but these drugs had considerably less effect on cell-free protein synthesis. The results indicate that the primary effect of the four drugs on protein synthesis is blocking of amino acid uptake by the cells.
Amino Acids↗
Targeting of hematin by the antimalarial pyronaridine.
Pyronaridine, 2-methoxy-7-chloro-10[3',5'-bis(pyrrolidinyl-1-methyl-)4'hydroxyphenyl]aminobenzyl-(b)-1,5-naphthyridine, a new Mannich base schizontocide originally developed in China and structurally related to the aminoacridine drug quinacrine, is currently undergoing clinical testing. We now show that pyronaridine targets hematin, as demonstrated by its ability to inhibit in vitro beta-hematin formation (at a concentration equal to that of chloroquine), to form a complex with hematin with a stoichiometry of 1:2, to enhance hematin-induced red blood cell lysis (but at 1/100 of the chloroquine concentration), and to inhibit glutathione-dependent degradation of hematin. Our observations that pyronaridine exerted this mechanism of action in situ, based on growth studies of Plasmodium falciparum K1 in culture showing antagonism of pyronaridine in combination with antimalarials (chloroquine, mefloquine, and quinine) that inhibit beta-hematin formation, were equivocal.
Animals↗
In vitro interactions between piperaquine, dihydroartemisinin, and other conventional and novel antimalarial drugs.
In an in vitro assessment of antimalarial combinations, dihydroartemisinin (DHA) showed no interaction or was mildly antagonistic when combined with piperaquine, pyronaridine, or naphthoquine. Interactions between 4-aminoquinolines and related drugs were also indifferent/antagonistic. The clinical significance of mildly antagonistic DHA combinations is uncertain but may become important if parasite drug sensitivity declines.
Animals↗
Role of P glycoprotein in absorption of novel antimalarial drugs.
Bidirectional transport of four novel antimalarial compounds was determined using Caco-2 cell monolayers. P glycoprotein-mediated efflux was greatest for pyronaridine (5 to 20 microM) and low for naphthoquine (5 microM). With 20 microM naphthoquine, net efflux was blocked, suggesting saturation of the transporter. Piperaquine and dihydroartemisinin were not transported by the system.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Estimating true antimalarial efficacy by heteroduplex tracking assay in patients with complex Plasmodium falciparum infections.
Heteroduplex tracking assays (HTAs) of Plasmodium falciparum merozoite surface protein 1 block-2 were used to assess complexity of infection and treatment efficacy in a trial of three antimalarial treatments in 141 Malawian pregnant women. An elevated complexity of infection (COI) was associated with anemia, parasite burden, and human immunodeficiency virus infection but was not associated with age or gravidity. Comparisons of HTA patterns before and after treatment allowed the classification of 20 of 30 (66%) recurrent episodes as either definite treatment failures or reinfections. An elevated COI was strongly associated with treatment failure (P=0.003). An algorithm was developed to assign a probability of failure for the 10 indeterminate participants, some of whose infections shared a single variant of high prevalence (>10%). By summing these probabilities, treatment efficacy was estimated.
Animals↗
Simple colorimetric inhibition assay of heme crystallization for high-throughput screening of antimalarial compounds.
Current assays for screening new antimalarials need initiators of beta-hematin formation that require laborious preparation, special devices, and substrates. In this study, based on reduction of heme absorption in beta-hematin formation, we developed a simple colorimetric assay using Tween 20 as an initiator and a microplate reader for high-throughput screening of inhibitors of beta-hematin formation.
Animals↗
Methodological issues in the assessment of antimalarial drug treatment: analysis of 13 studies in eight African countries from 2001 to 2004.
The objectives of these analyses were to assess the feasibility of the latest WHO recommendations (28-day follow-up with PCR genotyping) for the assessment of antimalarial drug efficacy in vivo and to examine how different statistical approaches affect results. We used individual-patient data from 13 studies of uncomplicated pediatric falciparum malaria conducted in sub-Saharan Africa, using chloroquine (CQ), sulfadoxine/pyrimethamine (SP), or amodiaquine (AQ). We assessed the use effectiveness and test performance of PCR genotyping in distinguishing recurrent infections. In analyzing data, we compared (i) the risk of failure on target days (days 14 and 28) by using Kaplan-Meier and per-protocol evaluable patient analyses, (ii) PCR-corrected results allowing (method 1) or excluding (method 2) new infections, (iii) and day 14 versus day 28 results. Of the 2,576 patients treated, 2,287 (89%) were evaluable on day 28. Of the 695 recurrences occurring post-day 14, 650 could be processed and 584 were resolved (PCR use effectiveness, 84%; test performance, 90%). The risks of failure on day 28 with Kaplan-Meier and evaluable-patient analyses tended to be generally close (except in smaller studies) because the numbers of dropouts were minimal, but attrition rates on day 28 were higher with the latter method. Method 2 yielded higher risks of failure than method 1. Extending observation to 28 days produced higher estimated risks of failure for SP and AQ but not for CQ (high failure rates by day 14). Results support the implementation of the current WHO protocol and favor analyzing PCR-corrected outcomes by Kaplan-Meier analysis (which allows for dropouts) and retaining new infections (which minimizes losses).
Africa↗
The antimalarial drug mefloquine binds to membrane phospholipids.
The new antimalarial drug mefloquine bound with high affinity (Kd approximately 3 X 10-7 M) to membrane lipids of normal mouse erythrocytes and of erythrocytes infected either with chloroquine-susceptible or chloroquine-resistant Plasmodium berghei. Approximately 80 nmol of mefloquine was bound per mg of total lipid. Mefloquine also bound to purified phospholipids with high affinity (Kd approximately 3 X 10-7 M). Phosphatidylinositol and phosphatidylserine bound 300 to 400 nmol of mefloquine per mg. Phosphatidylcholine and phosphatidylethanolamine bound approximately 100 nmol of mefloquine per mg. Mefloquine did not bind to hemoglobin with high affinity, but it bound to free ferriprotoporphyrin IX with a Kd of approximately 3 X 10-7 M. In comparison with mefloquine, chloroquine did not bind effectively to purified phospholipids, although it is known to bind with high affinity to free ferriprotoporphyrin IX. Greater binding to phospholipids may account for the superiority of mefloquine in the treatment of chloroquine-resistant malaria.
Animals↗
Crystal and molecular structure of the antimalarial agent 4-(tert-butyl)-2-(tert-butylaminomethyl)-6-(4-chlorophenyl)phenol dihydrogen phosphate (WR 194,965 phosphate).
WR 194,965 phosphate, a new antimalarial agent containing a biphenyl ring structure active against chloroquine-resistant Plasmodium falciparum, crystallized in ionic form with a positive charge on the quaternary nitrogen atom. The oxygen and nitrogen atoms of WR 194,965 were hydrogen bonded to the same phosphate group. The nitrogen atom was also hydrogen bonded to a second phosphate group. The phosphate ions formed discrete clusters of four phosphate moieties. The phosphate clusters contained fourfold inversion symmetry. The intramolecular N-O distance in WR 194,965 of 3.073 A (1 A = 0.1 nm) was close to the reported values for N-O distances in the active cinchona alkaloids and may be important for activity. A comparison of the crystalline structure of WR 194,965 with those of mefloquine and quinidine sulfate demonstrated that the regions of the three molecules in the vicinity of the aliphatic nitrogen atom and the oxygen atom superimpose. Much of the remainder of the WR 194,965 molecule spatially overlapped with the combined three-dimensional space defined by quinidine and mefloquine. The crystallographic parameters were: C21H29ClNO+.H2PO4-; Mr = 443.9; symmetry of unit cell, tetragonal; space group, I41/a; parameters of unit cell, a = b = 24.305 +/- 0.002 A, c = 17.556 +/- 0.003 A; V (volume of unit cell) = 10370.9 A3; Z (number of molecules per unit cell) = 16; Dx (calculated density) = 1.137 g cm-3; source of radiation, CuK alpha (lambda = 1.54178 A); mu (absorption coefficient) = 21.3 cm-1; F(000) (sum of atomic scattering factors at zero scattering angle) = 3,440; room temperature; final R = 8.2% for 2,508 reflections with [F0] greater than 3 sigma.
Animals↗
Potent antimalarial activity of the alkaloid nitidine, isolated from a Kenyan herbal remedy.
Bioassay-guided fractionation of extracts of Toddalia asiatica, a plant used by the Pokot tribe of Kenya to treat fevers, has yielded the alkaloid nitidine as the major antimalarial component. Fractions containing nitidine have in vitro 50% inhibitory concentrations against Plasmodium falciparum in the range of 9 to 108 ng/ml for a range of chloroquine-susceptible and -resistant strains. The results show a lack of cross-resistance between chloroquine and nitidine.
Animals↗
Quantitative assessment of antimalarial activities from Malaysian Plasmodium falciparum isolates by modified in vitro microtechnique.
Malaysian, TGR (Thailand), and Gambian (West African) Plasmodium falciparum isolates were cultured in vitro by the candle jar method and were characterized for their susceptibilities to present antimalarial drugs by the modified in vitro microtechnique. Results showed that 93 and 47% of the Malaysian isolates were resistant at 50% inhibitory concentrations of 0.1415 to 0.7737 and 0.1025 to 0.1975 microM, respectively, while the rest were susceptible to choloroquine and cycloguanil at 0.0376 and 0.0306 to 0.0954 microM, respectively. All isolates were susceptible to mefloquine, quinine, and pyrimethamine at 0.0026 to 0.0172, 0.0062 to 0.0854, and 0.0149 to 0.0663 microM, respectively. In contrast, the Gambian isolate was susceptible to multiple drugs at 0.0024 to 0.0282 microM; TGR was resistant to chloroquine at 0.8147 microM but was susceptible to mefloquine, quinine, cycloguanil, and pyrimethamine at 0.0024, 0.0096, 0.0143, and 0.0495 microM, respectively.
Animals↗
Potentiation of the antimalarial agent rufigallol.
We have discovered a remarkable synergistic antimalarial interaction between rufigallol and the structurally similar compound exifone. The synergistic effects were produced in chloroquine-susceptible and chloroquine-resistant clones of Plasmodium falciparum. The degree of potentiation as estimated by standard isobolar analysis was approximately 60-fold for experiments initiated with asynchronous parasites. The most pronounced synergism was observed in experiments with synchronized trophozoite-infected erythrocytes, in which the degree of synergy was at least 300-fold. While the mechanism underlying this drug potentiation remains unresolved, it is hypothesized that rufigallol acts in pro-oxidant fashion to produce oxygen radicals inside parasitized erythrocytes. These radicals would attack exifone, thereby initiating its transformation into a more potent compound, a xanthone.
Animals↗
Antimalarial and toxic effects of the acyclic nucleoside phosphonate (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine in Plasmodium berghei-infected mice.
Plasmodium berghei-infected mice died with low levels of parasitemia after repeated intraperitoneal administration (five times at 15 mg kg of body weight-1 every other day) of the in vitro active antimalarial acyclic nucleoside phosphonate (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA]. Toxicological studies showed that the main cause of death resulted from (S)-HPMPA-induced nephrotoxicity. Although concomitant intraperitoneal administration of the tubular epithelium transport blocker probenecid prevented (S)-HPMPA-induced toxicity, mice eventually died with a high level of parasitemia, despite repeated administration of high doses of (S)-HPMPA. The short half-life of (S)-HPMPA in plasma combined with the insusceptibility of the nonreplicative stages of the parasite to (S)-HPMPA could explain this failure to eradicate all parasites. Indeed, a low but sustained (calculated) level of 200 nM (S)-HPMPA in plasma completely cured P. berghei-infected mice. However, these mice, which received a total dose of only 28 mg kg-1 administered via osmotic pumps for 7 days, died because of the toxicity of the drug. These findings indicate that nephrotoxicity hinders the use of (S)-HPMPA as a drug against blood stage parasites. An alternative application of (S)-HPMPA as a potent prophylactic drug is discussed.
Adenine↗
In vitro antimalarial activity of penduline, a bisbenzylisoquinoline from Isopyrum thalictroides.
Two bisbenzylisoquinolines, tetrandrine and penduline, were purified from Isopyrum thalictroides. When tested for antimalarial activity in vitro, penduline was efficient at concentrations fivefold lower than those of tetrandrine. In highly synchronized parasite cultures, penduline mostly interfered between the 8th and the 32nd hours of the parasite cycle.
Alkaloids↗
Regulation of heme polymerizing activity and the antimalarial action of chloroquine.
Mice infected with Plasmodium berghei served as donors of erythrocytes with a high level of parasitemia for the study of ferriprotoporphyrin IX (FP) polymerization. Six hours after treatment of these mice with 3 micromol of chloroquine per 25 g of body weight, there were significant losses of heme polymerase I (HPA I). For chloroquine-susceptible (CS) P. berghei, the rate of FP polymerization decreased from 541 +/- 42 (mean +/- standard deviation; n = 12) to 51 +/- 19 (n = 8) nmol of FP polymerized per h per ml of packed erythrocytes (normalized to represent 1,000 parasites per 1,000 erythrocytes). For chloroquine-resistant (CR) P. berghei, the rate decreased from 284 +/- 19 (n = 16) to 124 +/- 11 (n = 6) nmol per h per ml. The chloroquine-induced loss of HPA I was accompanied by the accumulation of unpolymerized FP in CS P. berghei but not in CR P. berghei, which is consistent with the hypothesis that FP mediates the antimalarial action of chloroquine. Quinine treatment partially reversed the effects of chloroquine in CS P. berghei but not in CR P. berghei. Cycloheximide treatment antagonized the effects of chloroquine in both lines of parasites. To explain these findings, we propose that chloroquine, quinine, and cycloheximide perturb a regulatory process for HPA I. Furthermore, we propose that when chloroquine engages its target in the regulatory process, it initiates a chain of events which culminates in increased production, accessibility, or reactivity of a regulator (inactivator) of HPA I.
Animals↗
Relationship between antimalarial drug activity, accumulation, and inhibition of heme polymerization in Plasmodium falciparum in vitro.
We have investigated the contribution of drug accumulation and inhibition of heme polymerization to the in vitro activities of a series of antimalarial drugs. Only those compounds exhibiting structural relatedness to the quinolines inhibited heme polymerization. We could find no direct correlation between in vitro activity against chloroquine-susceptible or chloroquine-resistant isolates and either inhibition of heme polymerization or cellular drug accumulation for the drugs studied. However, in vitro activity against a chloroquine-susceptible isolate but not a chloroquine-resistant isolate showed a significant correlation with inhibition of heme polymerization when the activity was normalized for the extent of drug accumulation. The importance of these observations to the rational design of new quinoline-type drugs and the level of agreement of these conclusions with current views on quinoline drug action and resistance are discussed.
Animals↗
Effects of alpha-thalassemia on pharmacokinetics of the antimalarial agent artesunate.
Thalassemia is common in Southeast Asia, where artemisinin derivatives are frequently used in the treatment of malaria. It has been previously reported that artemisinin derivatives can be concentrated by uninfected thalassemic erythrocytes in vitro but not by normal erythrocytes. As a follow-up to this report, we studied the antimalarial kinetics of intravascular artesunate (2.4 mg/kg of body weight) in 10 persons with normal hemoglobins and in 10 patients with thalassemia (2 with alpha-thalassemia type 1-hemoglobin Constant Spring and 8 with alpha-thalassemia type 1-alpha-thalassemia type 2). Concentrations of artesunate and its active metabolites in plasma were measured by bioassay and expressed relative to those of dihydroartemisinin, the major biologically active metabolite. Concentrations of intravascular artesunate in plasma peaked in both the normal individuals and the thalassemic individuals 15 min after injection (the first time point). Plasma drug concentrations at all time intervals, except that at 1 h, were significantly higher in thalassemic subjects than in normal subjects (P < 0.05). The area under the concentration-time curve was 9-fold higher (P < 0.001) and the volume of distribution at steady state was 15-fold lower (P < 0.001) in thalassemic than in normal subjects. In light of the potential neurotoxicity of artemisinin derivatives, these results suggest that thalassemic subjects may need a drug administration regimen different from that of normal patients.
Adolescent↗