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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This report outlines the structure scheme and development of a new antimalarial drug pyronaridine, which was synthesized from either 2-aminopyridine or pyridine. A series of in vivo and in vitro experimental studies and the assessment of toxicity revealed pyronaridine to be a promising agent against erythrocytic stage of malaria parasites. It exhibited low toxicity and had no cross-resistance to chloroquine. Clinical administration in malaria cases showed high efficacy and mild side-effects. In order to retard the development of resistance of Plasmodium falciparum to pyronaridine, a combination of pyronaridine/sulfadoxine/pyrimethamine was used in the treatment of chloroquine-resistant falciparum malaria in Hainan Province. Further in vivo test was carried out to monitor the sensitivity of P. falciparum to this combined formula for 5 years (1986-1990) in Diaoluo area where chloquine-resistant falciparum malaria was prevalent. Drug resistance was not demonstrated in this field study.
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PMID:Development of the new antimalarial drug pyronaridine: a review. 164 89

In view of the antimalarial properties observed for many 2-acetylpyridine thiosemicarbazones, a series of N4,N4-disubstituted thiosemicarbazones derived from 2-propionyl-, 2-butyryl-, and 2-(2-methylpropionyl)pyridine was prepared for evaluation against the malaria parasite, Plasmodium berghei, in the mouse. The thiosemicarbazones were made by the reaction of methyl hydrazinecarbodithioate with a 2-acylpyridine to give the intermediate methyl 3-[1-2-pyridinyl)alkylidene]hydrazinecarbodithioates. Reaction of the latter with 3-azabicyclo[3.2.2]nonane, 1-(2-pyridinyl)piperazine, or 1H-hexahydroazepine gave the requisite thiosemicarbazones. The three thiosemicarbazones derived from 3-azabicyclo[3.2.2]nonane were most effective, the greatest potency being exhibited by 3-azabicyclo-[3.2.2]nonane-3-thiocarboxylic acid 2-[1-(2-pyridinyl)butylidene]hydrazide (4) which cured 4/5 mice at a dose of 160 mg/kg. In contrast to the related thiosemicarbazones derived from 2-acetylpyridine, virtually no toxic effects were observed in the series described here.
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PMID:2-Acetylpyridine thiosemicarbazones. 10. 2-Propionyl-, 2-butyryl-, and 2-(2-methylpropionyl)pyridine thiosemicarbazones as potential antimalarial agents. 639 97

This report describes an enzyme assay for the detection of Plasmodium falciparum. The assay is based on the observation that the lactate dehydrogenase (LDH) enzyme of P. falciparum has the ability to rapidly use 3-acetyl pyridine NAD (APAD) as a coenzyme in the reaction leading to the formation of pyruvate from lactate. Human red blood cell LDH carries out this reaction at a very slow rate in the presence of APAD. We measured the development of APADH and found that the formation of this product could establish the basis of an assay that detected the presence of P. falciparum from in vitro cultures at parasitemia levels of 0.02%. We also had occasion to use this assay with clinical samples. We found a correlation between levels of parasitemia and the activity of parasite LDH. Parasite LDH (pLDH) activity could be measured in blood hemolysates and in plasma and serum from patients with malaria. We used the serum assay for pLDH and followed the level of pLDH in a patient with cerebral malaria prior to antimalarial treatment and during the recovery period. From these initial studies, it is evident that the measurement of pLDH has a correlation with parasitemia and may offer a method that can be developed into a simple test for the detection of Plasmodium parasitemia.
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PMID:Measurement of the lactate dehydrogenase activity of Plasmodium falciparum as an assessment of parasitemia. 844 24

While studying the fate of heme generated during malaria infection, it was observed that mitochondrial preparations were highly enriched with heme compared to other subcellular particles. With this background, the present study aimed to determine the status of mitochondrial heme oxygenase and compare it with the microsomal enzyme. Mitochondrial and microsomal preparations were obtained from liver, spleen, kidney and brain of normal, inducer (cobalt chloride and hemin)-treated and Plasmodium berghei-infected Mastomys coucha. Heme oxygenase activity was determined by monitoring the formation of bilirubin. Biliverdin reductase activity was assayed by following the decrease in biliverdin content. Heme levels were measured by pyridine haemochromogen formation. Mitochondria from different tissues showed significant activity of heme oxygenase only after inducer (CoCl2 and hemin) treatment. In contrast, cerebral mitochondria did not show any enzyme activity. Hepatic, splenic and renal mitochondria of P. berghei-infected M. coucha showed noticeable heme oxygenase and biliverdin reductase activity. The response of hepatic mitochondrial heme oxygenase towards Triton X-100, trypsin, hydrogen peroxide, temperature, freezing and thawing and hemin was distinguishable from microsomal heme oxygenase. It is concluded that the mitochondria of different tissues from Mastomys display stress (biological and chemical)-induced activity of heme oxygenase. In addition, distinct differences between microsomal and mitochondrial heme oxygenase were observed.
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PMID:Mitochondrial heme oxygenase of Mastomys coucha. 893 Jan 30

The correlation of P. falciparum lactate dehydrogenase (pLDH) activities and patent infections was evaluated for monitoring therapeutic responses and drug resistance in 70 patients with microscopically confirmed P. falciparum malaria in Nigeria. Each patient was treated with standard dosages of artemether (53 patients), chloroquine (7 patients), sulfadoxine-pyrimethamine (6 patients), or halofantrine (4 patients). Response of infection to treatment was monitored by microscopic examination of thick and thin blood smears, clinical symptoms, and levels of pLDH activities in blood products. pLDH activity was determined using an antibody capture technique and 3-acetyl pyridine adenine dinucleotide developed to enhance sensitivity of the enzyme detection. All patients treated with artemether were cured while 5 patients treated with chloroquine, 1 treated with sulfadoxine-pyrimethamine, and 2 treated with halofantrine suffered recrudescent infections after treatment. pLDH activity was detected in blood products obtained from patients with patent or recrudescent infections determined by microscopy and clinical symptoms. Levels of pLDH activities in whole blood and packed cells from the patients correlated with qualitative detection of parasites in blood smears and in patients with high gametocyte counts. Gametocyte counts in the patients after treatment ranged from 40 gametocytes/microliter of blood to 4923 gametocytes/microliter of blood. There is a consistent relationship between patent infection and pLDH activities that could easily be determined in whole blood and packed cells from the patients. Further development of the procedure will enhance its valuable application in clinical management of drug-resistant malaria in the endemic areas.
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PMID:Plasmodium falciparum: evaluation of lactate dehydrogenase in monitoring therapeutic responses to standard antimalarial drugs in Nigeria. 937 Oct 95

Thioredoxin reductase (EC 1.6.4.5) is a widely distributed flavoprotein that catalyzes the NADPH-dependent reduction of thioredoxin. Thioredoxin plays several key roles in maintaining the redox environment of the cell. Like all members of the enzyme family that includes lipoamide dehydrogenase, glutathione reductase and mercuric reductase, thioredoxin reductase contains a redox active disulfide adjacent to the flavin ring. Evolution has produced two forms of thioredoxin reductase, a protein in prokaryotes, archaea and lower eukaryotes having a Mr of 35 000, and a protein in higher eukaryotes having a Mr of 55 000. Reducing equivalents are transferred from the apolar flavin binding site to the protein substrate by distinct mechanisms in the two forms of thioredoxin reductase. In the low Mr enzyme, interconversion between two conformations occurs twice in each catalytic cycle. After reduction of the disulfide by the flavin, the pyridine nucleotide domain must rotate with respect to the flavin domain in order to expose the nascent dithiol for reaction with thioredoxin; this motion repositions the pyridine ring adjacent to the flavin ring. In the high Mr enzyme, a third redox active group shuttles the reducing equivalent from the apolar active site to the protein surface. This group is a second redox active disulfide in thioredoxin reductase from Plasmodium falciparum and a selenenylsulfide in the mammalian enzyme. P. falciparum is the major causative agent of malaria and it is hoped that the chemical difference between the two high Mr forms may be exploited for drug design.
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PMID:Thioredoxin reductase two modes of catalysis have evolved. 1101 62

The ethyl 4-chlorobenzofuro[3,2-b]pyridine-3-carboxylate (2) reacted with the hydrochlorides of the mono- and bis-phenol Mannich bases 3 to yield the amodiaquine and pyronaridine analogues 4. The chloroquine analogue 6 was formed by melting 2 with the novaldiamine base (5) in phenol. The most active compound 4c inhibited the growth of the malaria parasite Plasmodium falciparum with an IC50 of 500 nM.
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PMID:[[1]Benzofuro[3,2-b]pyridin-4-yl-amines - synthesis and investigation of activity against malaria]. 1524 58

The ethyl 4-chlorobenzothieno[3,2-b]pyridine-3-carboxylate (2) reacted with the hydrochlorides of the mono- and bis-phenol Mannich bases 6 to yield the amodiaquine and pyronaridine analogues 9. The chloroquine analogue 10 was formed by melting 2 with the novaldiamine base (7) in phenol. The stability of the 4-aminophenols 9 was investigated by anodic oxidation using the rotating platinum electrode by means of difference pulse voltammetry. The half wave potentials were measured giving E(1/2) approximately 1.05 V. Compound 9g displayed the highest activity against the growth of the malaria parasite Plasmodium falciparum. Testing against the chloroquine sensitive 3D7 and the chloroquine resistant Dd2 strain resulted in IC50 values of 150 nM and 210 nM, respectively. Surprisingly, the 3-carbinol 4 and the 3-chloromethyl derivative 5, synthesized from the 3-carboxylic acid ester 2, reacted with the phenol Mannich base 6a and the novaldiamine base (7), respectively, to yield the 4-pyridone 8.
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PMID:[[1]Benzothieno[3,2-b]pyridin-4-yl-amine--synthesis and investigation of activity against malaria]. 1529 95

Antimalarial drugs such as chloroquine are believed to act by inhibiting hemozoin formation in the food vacuole of the malaria parasite. We have developed a new assay for measuring and detecting inhibition of synthetic hemozoin (beta-hematin) formation. Aqueous pyridine (5% v/v, pH 7.5) forms a low-spin complex with hematin but not with beta-hematin. Its absorbance obeys Beer's law, making it useful for quantitating hematin concentration in hematin/beta-hematin mixtures, allowing compounds to be investigated for inhibition of beta-hematin formation. The assay is rapid (60 min incubation) and requires no centrifugation. The beta-hematin inhibition data show good agreement with alternative assay methods reported by four laboratories. The assay was adapted for high-throughput colorimetric screening, allowing visual identification of beta-hematin inhibitors. In this mode, the assay successfully detected all 18 beta-hematin inhibitors in a set of 47 compounds tested, with no false positive results. The quantitative in vitro antimalarial activities of a set of 13 aminoquinolines and quinoline methanols were found to correlate significantly with beta-hematin inhibition values determined using the assay.
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PMID:A colorimetric high-throughput beta-hematin inhibition screening assay for use in the search for antimalarial compounds. 1574 52

The strength of inhibition of beta-hematin (synthetic hemozoin or malaria pigment) formation by the quinoline antimalarial drugs chloroquine, amodiaquine, quinidine and quinine has been investigated as a function of incubation time. In the assay used, beta-hematin formation was brought about using 4.5M acetate, pH 4.5 at 60 degrees C. Unreacted hematin was detected by formation of a spectroscopically distinct low spin pyridine complex. Although, these drugs inhibit beta-hematin formation when relatively short incubation times are used, it was found that beta-hematin eventually forms with longer incubation periods (<8h for chloroquine and >8h for quinine). This conclusion was supported by both infrared and X-ray powder diffraction observations. It was further found that the IC(50) for inhibition of beta-hematin formation increases markedly with increasing incubation times in the case of the 4-aminoquinolines chloroquine and amodiaquine. By contrast, in the presence of the quinoline methanols quinine and quinidine the IC(50) values increase much more slowly. This results in a partial reversal of the order of inhibition strengths at longer incubation times. Scanning electron microscopy indicates that beta-hematin crystals formed in the presence of chloroquine are more uniform in both size and shape than those formed in the absence of the drug, with the external morphology of these crystallites being markedly altered. The findings suggest that these drugs act by decreasing the rate of hemozoin formation, rather than irreversibly blocking its formation. This model can also explain the observation of a sigmoidal dependence of beta-hematin inhibition on drug concentration.
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PMID:Quinoline antimalarials decrease the rate of beta-hematin formation. 1592 60


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