High Antimalarial Activity Research Articles

Preparation and Antimalarial Activities of “Trioxaquines”, New Modular Molecules with a Trioxane Skeleton Linked to a 4-Aminoquinoline

Trioxaquines are new antimalarial drugs which combine two active fragments (an aminoquinoline and a trioxane) with independant modes of action covalently linked within a single molecule. This strategy, which can be characterized as a “covalent bitherapy”, allowed us to obtain modular molecules with high antimalarial activity in vitro either on chloroquine sensitive or on chloroquine resistant Plasmodium falciparum strains.

Preparation and antimalarial activities of "trioxaquines", new modular molecules with a trioxane skeleton linked to a 4-aminoquinoline.

Trioxaquines are new antimalarial drugs which combine two active fragments (an aminoquinoline and a trioxane) with independant modes of action covalently linked within a single molecule. This strategy, which can be characterized as a “covalent bitherapy”, allowed us to obtain modular molecules with high antimalarial activity in vitro either on chloroquine sensitive or on chloroquine resistant Plasmodium falciparum strains.

Antimalarial activity of four plants used in traditional medicine in Mali.

Mitragyna inermis (De Willd.) O. Kuntze Rubiaceae, Nauclea latifolia (Sm.) Rubiaceae, Glinus oppositofolius (Linn) Molluginaceae and Trichilia roka (Forsk.) Chiv. Meliaceae were investigated for their in vitro antimalarial activity. Leaves, roots and stem barks were submitted to aqueous, hydromethano and chloroform extractions and antimalarial activity was evaluated by microscopic and flow cytometric analysis. The results present evidence that the alkaloids contained in chloroform extracts and ursolic acid, purified from the hydromethanol extract of M. inermis induced a significant decrease of parasite proliferation. However, aqueous extracts, traditionally used for medication did not show high antimalarial activity. Statistical comparison between microscopic and cytometric analysis demonstrated the validity of this new technique for the screening of active antimalarial compounds isolated from plants.

Correlating the molecular electrostatic potentials of some organic peroxides with their antimalarial activities.

The molecular electrostatic potentials (MEPs) of artemisinin (also known as qinghaosu), yingzhaosu A, and some synthetic analogues have been calculated and studied as a means of distinguishing between high and low antimalarial activity. To facilitate comparison, the dimensionality of the MEP was reduced by Kohonen Neural Network transforms. The reduction revealed that peroxides exhibiting high antimalarial activity are characterized by a continuous strip of negative electric potential surrounding the molecule, whereas peroxides of lesser activity show a broken strip.

First Total Synthesis of Dioncophylline B, a 7,6′-Coupled Naphthylisoquinoline Alkaloid

The total synthesis of dioncophylline B (2), a naphthylisoquinoline alkaloid with the rare 7,6′-coupling type and high antimalarial and fungicidal activities, is described. The key step of this convergent synthesis is the regioselective intermolecular biaryl coupling of its appropriately modified naphthalene and isoquinoline moieties, with MOM-functionalized oxygen substituents next to the coupling sites: The naphthalene moiety is activated by a directed ortho-metalation → stannylation procedure, while the isoquinoline part is metalated and then brominated ortho to the MOM-protected oxygen function, thus allowing a Stille coupling to connect the two parts. The work constitutes the first synthesis of any 7,6′-coupled naphthylisoquinoline alkaloid.

Antimalarial activity of macrocyclic trichothecenes isolated from the fungus Myrothecium verrucaria.

Bioassay-guided fractionation of an extract from the fungus Myrothecium verrucaria BCC 112 resulted in the first isolation of roridin E acetate (5) from nature together with four common macrocyclic trichothecene isomers (1-4). Trichothecenes 1-5, while known as mycotoxins, were evaluated for their high antimalarial activity.

Submicron oil-in-water emulsion formulations for mefloquine and halofantrine: effect of electric-charge inducers on antimalarial activity in mice.

Stearylamine, oleic acid, phosphatidylserine and dicetylphosphate have been studied to determine their capacity to induce electric charge on non-ionic submicron emulsions containing halofantrine and mefloquine. The in-vivo antimalarial activity of drug-loaded emulsions, evaluated in mice, was affected by the nature of the additives used. In particular, the electric-charge inducers markedly affected the pharmacological activity of mefloquine, but not of halofantrine. After subcutaneous administration ED50 values (the doses affording 50% protection) were 3 and 15 mg kg(-1), respectively, for halofantrine and mefloquine emulsions without charge inducers. The mefloquine-loaded emulsions with charge inducers were active at 10 mg kg(-1) for dicetylphosphate, 17 mg kg(-1) for phosphatidylserine, 23 mg kg(-1) for oleic acid and 27 mg kg(-1) for stearylamine, again after subcutaneous administration. This work has enabled the formulation of stable emulsions, incorporating drugs with high antimalarial activity, which are proposed for parenteral delivery of these fairly soluble drugs.

Synthesis and antimalarial activity in vitro and in vivo of a new ferrocene-chloroquine analogue.

The antimalarial activities of ferrocenic compounds mimicking chloroquine and active upon chloroquine-resistant strains of Plasmodium falciparum were evaluated. Four 7-chloro-4-[[[2-[(N,N-substituted amino)methyl]ferrocenyl]methyl]amino]quinoline derivatives have been synthesized; one of them, 1a, showed high potent antimalarial activity in vivo on mice infected with Plasmodium berghei N. and Plasmodium yoelii NS. and was 22 times more potent against schizontocides than chloroquine in vitro against a drug-resistant strain of P. falciparum.

ChemInform Abstract: Acetogenic Isoquinoline Alkaloids. Part 87. Antiprotozoal Activity of Naphthylisoquinoline Alkaloids. Part 6. Jozimine A (“Dimeric” Dioncophylline A), a Non‐Natural Michellamine Analogue with High Antimalarial Activity.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Chemical Investigation and in vitro Antimalarial Activity of Tabebuia ochracea ssp. neochrysantha

A study of Tabebuia ochracea ssp. neochrysantha, a plant traditionally used in the Amazon against malaria, was pursued. Bioactivity was tested in vitro against Plasmodium berghei and Plasmodium falciparum (FcB2 chloroquine-resistant strain). Inhibitory activity was determined by measuring parasite 3 H-hypoxanthine incorporation. Fractionation of the chloroformic extract of P. ochracea (inner stem bark) afforded five furanonaphthoquinones. The highest antimalarial activity against P. berghei was given by a mixture of two compounds which could not be separated, but the isomeric structures of 5- and 8-hydroxy-2-(1'-hydroxy)-ethyl-naphtho-[2,3-b]-furan-4,9-dione (1 and 2) were determined from spectroscopic data. The 50% inhibitory concentration (IC 50) values obtained with the mixture of compounds 1 and 2 were 1.67 x 10 –7 M for P. berghei and 6.77 x 10 –7 for the FcB2 chloroquine-resistant strain of P. falciparum. For the former parasite, the IC 50 value for chloroquine was 5 x 10 –8 M. That for P. falciparu...

Jozimine A (‘dimeric’ dioncophylline A), a non-natural michellamine analog with high antimalarial activity

Abstract The synthesis of jozimine A, the first non-natural dimer of a naturally occurring monomeric naphthylisoquinoline alkaloid, is described, starting from dioncophylline A, as isolated from Triphophyllum peltatum , resp. prepared by total synthesis. It is the first dimeric naphthylisoquinoline alkaloid that displays distinct antimalarial activity (IC 50 = 0.075 μg/ml) against asexual erythrocytic stages of Plasmodium falciparum , which even exceeds the activity of its monomeric precursor, dioncophylline A (IC 50 = 1.44 μg/ml), and thus constitutes a novel type of antimalarial quateraryls.

Tanzanian medicinal plants used traditionally for the treatment of malaria: In vivo antimalarial and in vitro cytotoxic activities

AbstractSeventeen fractions of extracts obtained from 11 Tanzanian medicinal plants, which had previously been shown to possess a high antimalarial activity in vitro were submitted to the 4‐day suppressive test in Plasmodium berghei‐infected mice, and were investigated for cytotoxic activity in human carcinoma cell lines in vitro. Several fractions administered orally to the mice (500 mg/kg body weight/day) produced a significant reduction of parasitaemia. The most effective plant fractions investigated were those of the root and stem bark of Maytenus senegalensis (90% and 63% suppression of parasitaemia, respectively) and of the roots of Cissampelos mucronata (59% suppression). Highest cytotoxic activities were found with all fractions of Maytenus senegalensis (IC50 1 μg/mL) and with the PE fraction of the roots of Salacia madagascariensis (median IC50=1.2 μg/mL for HT 29 and 2.3 μg/mL for KB).

Further evidence supporting the importance of and the restrictions on a carbon-centered radical for high antimalarial activity of 1,2,4-trioxanes like artemisinin.

Further evidence supporting the importance of and the restrictions on a carbon-centered radical for high antimalarial activity of 1,2,4-trioxanes like artemisinin.

Pharmacokinetics of arteether in dog

A pharmacokinetic study has been conducted in six beagle dogs after i.m. administration of 25 mg/kg of arteether, a qinghaosu (artemisinin) derivative of high anti-malarial activity. Arteether plasma concentrations were measured during a 24 h period using HPLC with an electrochemical detector in the reductive mode. The pharmacokinetic parameters were established using an open two-compartment model. Results showed a relatively rapid absorption phase: T1/2ka was 0.300 +/- 0.096 h and a mean elimination half-life of 27.95 +/- 11.93 h. Cmax was 110 +/- 16 ng/ml, Cltot/F was 1.69 +/- 0.34 ml/min and AUC was 2797 +/- 476 ng/ml/h.

Antimalarial activity of new water-soluble dihydroartemisinin derivatives. 3. Aromatic amine analogs

A series of artemisinin (1) derivatives containing bromo and heterocyclic or aromatic amine functions was prepared in the search for analogues with good water solubility and high antimalarial activity. Treatment of dihydroartemisinin (2a) with boron trifluoride etherate at room temperature gave the key intermediate, 9,10-dehydrodihydroartemisinin (3), which, on reaction with bromine, gave the dibromide 4. The latter was condensed with amines in anhydrous CH2Cl2 at less than -10 degrees C to give the desired products in 25-55% yield. The new derivatives, tested in vitro against Plasmodium falciparum, were found to be more effective against W-2 than D-6 clones and were not cross-resistant with existing antimalarials. Compound 6b, 3-fluoroaniline derivative, was the most active of the series, with the IC50 less than or equal to 0.16 ng/mL, making it several fold more potent than 1. However, no significant in vivo antimalarial activity against Plasmodium berghei was observed in any of the new compounds tested.

Schizontocidal Activity of Antibiotics Against Blood-Induced <i>Plasmodium gallinaceum</i> Infection

Comparative studies on the blood schizontocidal activity of antibiotics against Plasmodium gallinaceum infection of chicks have shown that doxycycline, minocycline, demeclocycline, tetracycline and oxytetracycline possess high antimalarial activity as judged by suppression of parasitaemia and extension of survival period. Of these, demeclocycline, tetracycline and oxytetracycline were effective only at high dose level. Chloramphenicol, erythromycin and gentamicin were relatively inactive. Treatment in 5- to 6-day-old established infection of chicks has shown that doxycycline and minocycline are relatively more effective than oxytetracycline and tetracycline in controlling acute infection.

Daraprim resistance in experimental malarial infections.

‘DARAPRIM’ [2 : 4-diamino-5-(-4′-chlorophenyl)-6-ethyl pyrimidine (50–63) ] has been described1 as having high antimalarial activity in laboratory infections of Plasmodium gallinaceum, Plasmodium berghei and Plasmodium cynomolgi. More recently, it has also been tried in the treatment and suppression of human malaria2. It has been shown that proguanil-resistant strains of the first two species are sensitive to ‘Daraprim’ and that ‘Daraprim’ resistance is not easily produced in P. gallinaceum infections3.

A metabolite of paludrine with high antimalarial activity.

SINCE the discovery of ‘Paludrine’ (proguanil, N1-p-chlorophenyl-N5-isopropyldiguanide) by Curd, Davey and Rose1, considerable evidence has accumulated that this drug probably differs in its mode of action from most other antimalarials. Direct evidence that proguanil is transformed in the animal body into another, more active, compound was provided by Hawking2 and Hawking and Perry3, who showed that proguanil has no action on in vitro cultures of the exo-erythrocytic forms of Plasmodium gallinaceum or on the blood forms of P. cynomolgi, whereas, under similar conditions, serum from animals dosed with the drug has high antimalarial activity.

AN ALKALOID WITH HIGH ANTIMALARIAL ACTIVITY FROM DICHROA FEBRIFUGA1

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAN ALKALOID WITH HIGH ANTIMALARIAL ACTIVITY FROM DICHROA FEBRIFUGA1J. B. Koepfli, J. F. Mead, and John A. Brockman Jr.Cite this: J. Am. Chem. Soc. 1947, 69, 7, 1837Publication Date (Print):July 1, 1947Publication History Published online1 May 2002Published inissue 1 July 1947https://doi.org/10.1021/ja01199a513RIGHTS & PERMISSIONSArticle Views428Altmetric-Citations169LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (153 KB) Get e-Alerts Get e-Alerts

The synthesis of chemotherapeutic agents. I.: The synthesis of certain thio and dithio compounds

Investigation of 5,5′-diacetamido-8,8′-diquinolyl disulfide indicated that it possesses a relatively high antimalarial activity. The report of this activity stimulated interest in the possible chemotherapeutic value of certain related thio and dithio compounds. This paper, the first of a series, describes the synthesis of sixteen compounds, eight of which are new, related to 5,5′-diacetamido-8,8′-diquinolyl disulfide. Twelve of these compounds were tested for antimalarial activity and the results of these tests are tabulated. In addition some of the compounds were also subjected to screening tests against Trypanosoma brucei, influenza virus and tetanus toxin.