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A search for natural bioactive compounds in Bolivia through a multidisciplinary approach. Part V. Evaluation of the antimalarial activity of plants used by the Tacana Indians.

One hundred and twenty-five extracts of 122 different plant species traditionally used by the Tacana, a native community living in lowland forest at the base of the last foothills of the Cordillera Oriental of the Bolivian Andes, were screened for antimalarial activity in vitro on Plasmodium falciparum chloroquine resistant (D2) and sensitive strains (F32), and were evaluated in vivo on rodent malaria Plasmodium berghei. Five ethanolic stembark extracts showed marked activity either in vitro or in vivo, and only one of them, Bowdichia virgilioides being traditionally used against malaria, was active in vitro (IC50=1 microg/ml on both strains) and in vivo (51% at 100 mg/kg). Other active extracts were from Caesalpinia pluviosa bark displaying activity in vitro against chloroquine resistant strain (IC50 8.3 microg/ml), traditionally used against dysentery; two Lauraceae bark extracts, Nectandra aff. hihua and Licaria canella respectively used for construction purposes and against stomach ache, both displaying activity in vitro against P. falciparum sensible and resistant strains (IC50 around 4 microg/ml); finally, the bark of a strongly aromatic Burseraceae, Protium glabrescens exuding an anti-inflammatory and analgesic resin, was active in vivo only (61% at 100 mg/kg). Results are discussed in relation with Tacana traditional medicine.

Animals↗

Antimalarial activity of medicinal plants used in traditional medicine in S. Tomé and Príncipe islands.

The present study investigates the antimalarial activity of 13 medicinal plants used in traditional medicine in S. Tomé and Príncipe (STP) islands in the Gulf of Guinea, aiming at identifying the most effective plants for further research. Fieldwork was carried out with the collaboration of 37 traditional healers from both islands, during an ethnobotanical study, which was conducted from 1993 to 1999. Our results indicate that the traditional healers in STP use several medicinal plants against fever and/or 'malaria' which reveal strong antiparasitic activity in vitro: four of the plant extracts have evident antiplasmodial activity against chloroquine resistant Plasmodium falciparum, with IC(50) values <10 microg/ml, and also revealed hepatic schizontocidal activity (<5-35 microg/ml). In vivo, the extracts caused partial reduction of Plasmodium berghei parasitaemia in mice.

Animals↗

A colorimetric field method to assess the authenticity of drugs sold as the antimalarial artesunate.

Artesunate is the most widely used of the artemisinin derivatives. These drugs are being used increasingly throughout the tropical world, and are an essential component of the treatment of multi-drug resistant malaria. The recent and widespread appearance of counterfeit artesunate tablets in several countries in Southeast Asia poses a serious threat to health in this region. We have developed a simple, inexpensive colorimetric test to determine artesunate authenticity in tablets. The test is based on a reaction between an alkali decomposition product of artesunate and a diazonium salt, fast red TR (FRTR). The appearance of a yellow color indicates the presence of artesunate. The specificity of the test is dependent on the pH of the reaction. Among other antimalarials tested, (i.e. artemisinin, artemether, chloroquine, quinine, primaquine, sulfadoxine, and pyrimethamine) only artesunate produced a positive color reaction at pH 4. The assay requires only 1% of the total weight of a standard tablet containing 50 mg of artesunate and can be completed within 10 min. The method was tested on six genuine artesunate tablets and six counterfeit artesunate tablets obtained in Southeast Asia. The average amount of artesunate in the genuine tablets was determined to be 50.8 +/- 2.9 mg while the counterfeit tablets were found to contain no artesunate.

Antimalarials↗

Conductometric and indirect AAS determination of antimalarials.

Two methods are described for the determination of amodiaquine hydrochloride, chloroquine phosphate and primaquine phosphate, based on the formation of their ion-associates with [Cd(2+), Co(2+), Mn(2+) and Zn(2+)] thiocyanate, ammonium reineckate and/or sodium cobaltinitrite. The molar combining ratio reveal that (1:1) (drug:reagent) ion associates are formed for all reagents except for ammonium reineckate which form (1:2) ion associates with all studied drugs. The optimum conditions for the ion-association have been studied. Conductometric method was applied for the direct determination of the suggested drugs in bulk powders, whereas indirect atomic absorption spectrometric method, depending on the measurement of the excess metal ion present in supernatant solutions after precipitation of the ion associates is used to calculate the drug concentration. Optimum concentration ranges for the determination of aminoquinoline antimalarial drugs under consideration were 0.46-12.90 and 0.155-3.87 mg using conductometric and indirect atomic absorption spectral methods, respectively. The proposed procedures have been applied successfully to the analysis of these drugs in certain formulations and the results are favourably comparable to the official methods.

Antimalarials↗

A rapid and sensitive high performance liquid chromatographic assay of the new antimalarial compound 80/53 in serum with a novel sample clean-up method and its pharmacokinetics in rabbits.

The compound 80/53 (AM) is a new antimalarial agent synthesized by this institute as a safer and less toxic analogue of primaquine. It was found to exhibit fluorescence in acetonitrile solution and this finding was exploited to develop a selective and sensitive high performance liquid chromatographic (HPLC) assay of the AM in rabbit serum. The sample clean-up was done in a single step by simultaneous protein precipitation and extraction with acetonitrile in the presence of sodium sulfate. The lower limit of quantitation of the method was 50 ng ml-1 using 100 microliters of serum sample. The method was fully validated from 50 to 1600 ng ml-1 concentration range with a recovery ranging from 70 to 75%. The within- and between-run variability was less than 10% and the drug in serum was stable over four freeze-thaw cycles and up to 24 h in injection solvent at 4 degrees C. The method was applied to determine the pharmacokinetic parameters of AM in 5 rabbits receiving a single bolus intravenous and peroral dose in a crossover study. The concentration-time data after a 5 mg kg-1 i.v. dose in rabbits was best fitted to the two compartment body model with first order absorption and elimination rate constants. The terminal half-life and MRT of AM were 95.3 +/- 43.5 and 104 +/- 10.6 min respectively. After administering a single 20 mg kg-1 oral dose, the serum levels of AM in all the rabbits declined below the quantitation limit by 90 min and it was not possible to fit the data by the compartmental approach. The MRT and AM after oral dose was 31.1+2-8.3 min. Application of the assay has also been extended to analyze the serum samples of rats, monkeys and humans.

Animals↗

Antimalarials.

Antimalarial medications have become the parenteral drugs of choice for treating the cutaneous manifestations of lupus erythematosus. The immune-modulating activity of these agents makes them useful in a variety of other dermatoses. With prudent dosage and monitoring, these agents can be used safely and effectively in the treatment and management of dermatologic disease.

Antimalarials↗

Case study: neuropsychiatric symptoms associated with the antimalarial agent mefloquine.

The development of acute neuropsychiatric symptoms in a 10-year-old boy subsequent to his return from travel abroad in Africa, where he had taken the antimalarial agent mefloquine (Lariam), is reported. A 4-week course of cognitive-behavioral therapy was used to effectively treat this substance-induced anxiety disorder, which had been caused by treatment with mefloquine. A review of the literature about adverse neuropsychiatric effects of mefloquine and the differential diagnosis of malaria is provided. In an age in which international travel is occurring with increasing frequency, it is important to obtain travel histories, including exposure to prophylactic medication, when patients present with acute-onset psychiatric symptoms.

Antimalarials↗

Caffeine and nicotinamide enhances the aqueous solubility of the antimalarial agent halofantrine.

The aqueous solubility of the antimalarial agent halofantrine in phosphate buffers pH 5.9 and 7.0 (ionic strength 0.08) is increased by the addition of caffeine and nicotinamide. Solubility is increased to a greater extent in the presence of caffeine (12.5-125 mM) than nicotinamide (125 mM -2.0 M). The greatest increase in solubility was observed at pH 5.9 where the basal solubility of halofantrine rose from 0.91 to 435 microM when 125 mM caffeine was added. Phase solubility studies support the formation of a 1:1 complex between caffeine and halofantrine which is characterised by a K(1:1) constant of 2.75x10(3) M(-1) (pH 5.9). A less stable 1:1 complex is formed at pH 7.0 (K(1:1)=6.37x10(3) M(-1)). Differential scanning calorimetry of solid mixtures of caffeine and halofantrine showed the absence of the endotherms of the two drugs and the appearance of a distinct endotherm (with a smaller enthalpy) characteristic of the complex. An analysis of the 1H-NMR spectra of mixtures of caffeine and halofantrine revealed perturbations in the chemical shifts of the methyl group and proton at positions 4 and 8 of caffeine, and a change in splitting pattern of the H(9) proton of the phenanthrene ring in halofantrine.

Antimalarials↗

Oxygenated chalcones and bischalcones as potential antimalarial agents.

Oxygenated chalcones (3a,b) and bischalcones (4a-j) have been synthesized and evaluated for antimalarial activity against chloroquine sensitive and resistant strains of Plasmodium berghei in mice. Some of the screened compounds, 3a, 4c, 4e, 4f and 4i, have shown significant activity at 100 mg/kg dose against sensitive strain.

Animals↗

Peptidomimetic inhibitors of protein farnesyltransferase show potent antimalarial activity.

Malaria continues to represent a very serious health problem in the tropics. The current methods of clinical treatment are showing deficiencies due to the increased incidence of resistance in the parasite. In the present paper we report the design, synthesis, and evaluation of potential antimalarial agents against a novel target, protein farnesyltransferase. We show that the most potent compounds are active against Plasmodium falciparum in vitro at submicromolar concentrations.

Alkyl and Aryl Transferases↗

Diaryl ester prodrugs of FR900098 with improved in vivo antimalarial activity.

The fosmidomycin derivative FR900098 represents an inhibitor of the 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase with potent antimalarial activity. Prodrugs of FR900098 with increased activity after oral administration were obtained by chemical modification of the phosphonate moiety to yield phosphodiaryl esters. One diaryl ester prodrug demonstrated efficacy in mice infected with the rodent malaria parasite Plasmodium vinckei comparable to i.p. drug administration.

Aldose-Ketose Isomerases↗

Design, synthesis, and biological evaluation of a series of simple and novel potential antimalarial compounds.

A series of compounds bearing an endocyclic -N-O- moiety with potential antimalarial activity based on simple derivatives of the tropolone purpurogallin was prepared by means of a hetero Diels-Alder reaction using nitrosobenzene as a dienophile. The rationale behind the design of these compounds is presented, together with the synthetic route to derivatives bearing aromatic and aliphatic esters of the C4'-position hydroxyl group of the purpurogallin framework, as well as biological data obtained from in vitro assays against Plasmodium falciparum and Trypanosoma cruzi. Several of the new compounds have activities in the 3-9 microM range, and provide leads for the development of a novel class of antiparasitic drugs with improved biological and pharmacological properties.

Animals↗

Antimalarial halorosellinic acid from the marine fungus Halorosellinia oceanica.

Three known compounds, 2-hexylidene-3-methylsuccinic acid (1), cytochalasin Q (2), and 5-carboxymellein (3), together with two new derivatives, 2-hexylidene-3-methylsuccinic acid 4-methyl ester (4) and an ophiobolane sesterterpene named halorosellinic acid (5), were isolated from culture broth of the marine fungus Halorosellinia oceanica BCC 5149. Compounds 1-3 exhibited moderate cytotoxicity against KB and BC-1 cell lines with IC(50) values of 1-13 microg/mL, while compounds 2, 3, 5, and 6 showed antimalarial activity with respective IC(50) values of 17, 4, 13, and 19 microg/mL. Halorosellinic acid (5) possessed only weak antimycobacterial activity with the minimum inhibitory concentration of 200 microg/mL.

Animals↗

Synthesis and evaluation of new antimalarial analogues of quinoline alkaloids derived from Cinchona ledgeriana Moens ex Trimen.

In the course of attempts to develop antimalarial drugs, we have designed and synthesized a series of quinoline alkaloide derivatives. Three of them, N-(4-methoxy-3,5-di-tert-butylbenzyl)cinchonidinium bromide (OSL-5), O-benzyl-N-(3,5-di-tert-butyl-4-methoxybenzyl)cinchonidinium bromide (OSL-7), and N-(3,5-di-tert-butyl-4-methoxybenzyl)quininium bromide (OSL-14) show potent activity against Plasmodium falciparum.

Animals↗

Antimalarial activities of ring-substituted bioimidazoles.

We report in vitro antimalarial activities against chloroquine sensitive and resistant Plasmodium falciparum strains, and in vivo activities against Plasmodium berghei in mice for four series of ring-substituted-L-histidines and histamines.

Animals↗

Antimalarial activity of ferrocenyl chalcones.

A series of ferrocenyl chalcones were synthesized and evaluated for in vitro antimalarial activity against a chloroquine-resistant strain of Plasmodium falciparum. The most active compounds were 1-(3-pyridyl)-3-ferrocenyl-2-propen-1-one (6) and 1-ferrocenyl-3-(4-nitrophenyl)-2-propen-1-one (28) with IC(50) of 4.5 and 5.1 microM, respectively. Differences in activity were not readily explained by the size and lipophilicity characteristics of these compounds.

Animals↗

Solid-phase synthesis and bioevaluation of lupeol-based libraries as antimalarial agents.

The use of the triterpenoid lupeol as a scaffold for the synthesis of lupeol-based libraries is described. Lupeol was anchored to a solid support (Rink amide/Sieber Amide) through aliphatic dicarboxylic acid moieties, which also served as a site for introducing diversity. The resulting polymer linked 3beta-O (resin-alkanoyl)-lup-20(29)-ene 3 was used to generate key intermediates 3beta-O (resin-alkanoyl)-30-bromo-lup-20(29)-ene 4 and 3beta-O (resin-alkanoyl)-30-amino-lup-20(29)-ene 6 for the generation of libraries based on disubstituted lupeol derivatives. A 96-member library was screened for its in-vitro antimalarial activity against Plasmodium falciparum.

Animals↗

Isolation and antimalarial activity of peroxydisulfate oxidation products of primaquine.

Five compounds formed by peroxydisulfate oxidation of primaquine were isolated using chromatographic methods and evaluated for antimalarial activity in vitro. One compound 6-methoxy-5,8 bis(4'-amino-1'-methylbutylamino)quinoline [P(1)] was found to have good gametocytocidal activity against Plasmodium yoelli infected mice at 10mg kg(-1) dose in vivo.

Animals↗