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PubMed2004

3D QSAR studies on antimalarial alkoxylated and hydroxylated chalcones by CoMFA and CoMSIA.

The 3D QSAR analyses of antimalarial alkoxylated and hydroxylated chalcones were first conducted by Comparative molecular field analysis (CoMFA) and Comparative similarity indices analysis (CoMSIA) to determine the factors required for the activity of these compounds. Satisfactory results were obtained after performing a leave-one-out (LOO) cross-validation study with cross-validation q(2) and conventional r(2) values of 0.740 and 0.972 by the CoMFA model, 0.714 and 0.976 by the CoMSIA model, respectively. The results provided the tools for predicting the affinity of related compounds, and for guiding the design and synthesis of novel and more potent antimalarial agents.

Antimalarials↗
PubMed2005

Non-thiol farnesyltransferase inhibitors: N-(4-aminoacylamino-3-benzoylphenyl)-3-[5-(4-nitrophenyl)-2 furyl]acrylic acid amides and their antimalarial activity.

Water solubility was previously found to be essential for in vivo-antimalarial activity of a novel type of benzophenone-based farnesyltransferase inhibitors. Introduction of a alpha-amino group into the phenylacetic acid substructure provided more soluble compounds with high farnesyltransferase inhibitory activity. The in vitro-antimalarial activity was detrimentally influenced by this structural modification.

Acrylamides↗
PubMed2005

Synthesis and antimalarial activity of E-2-quinolinylbenzocycloalcanones.

A series of E-2-quinolinylbenzocycloalcanones 5-21 were prepared and evaluated for their activity to inhibit beta-hematin formation and the hydrolysis of hemoglobin in vitro. Positive compounds for both assays were also tested for their efficacy in rodent Plasmodium berghei. Compounds 6, 16, 19, and 20, were the most promising. Inhibition of beta-hematin formation was minimal when a hydrogen or methoxy groups were present on the position 8 of the quinoline and position 4' of the indanone ring as it appeared for compounds 5, 7-15, 17, 18, and 21, and greatest with compounds (52%) and (90%) with a substitution of methoxy on position 6 and 7 or methyl on position 8 of the quinoline nucleus and methoxy or methyl groups on position 4' of the indanone. The most active compound to emerge from this study is 2-chloro-8-methyl-3-[(4'-methoxy-1'-indanoyl)-2'-methyliden]-quinoline 20 effective as antimalarial that target beta-hematin formation and the inhibition of the hydrolysis of hemoglobin in vitro together with a good survival in a murine malaria model, which should help delay the rapid onset of resistance to drugs acting at only a single site. Results with these assays suggest that quinolinylbenzocycloalcanones exert their antimalarial activity via multiple mechanisms.

Animals↗
PubMed2005

Synthesis and antimalarial activities of some furoxan sulfones and related furazans.

Furoxan derivatives bearing a sulfone moiety at position 3 or 4 were synthesized and tested for their antimalarial action on the chloroquine-sensitive D10 and the chloroquine-resistant W2 strains of Plasmodium falciparum. The furazan analogues were considered for comparison. The most active compounds were the products in which the -SO2R groups are at the 3-position of the furoxan system. These latter substances displayed an antimalarial activity in the microM range, possibly related in part to their ability to release NO.

Animals↗
PubMed2006

Arylmethyl substituted derivatives of Fosmidomycin: synthesis and antimalarial activity.

The phosphonohydroxamic acid Fosmidomycin is a drug candidate for the treatment of Malaria, currently in phase II trials in combination with Clindamycin. In order to obtain compounds of higher lipophilicity, we recently synthesized alpha-phenyl substituted Fosmidomycin derivatives which display high antimalarial activity. We now report the synthesis and in vitro antimalarial activity of arylmethyl substituted bis(pivaloyloxymethyl) ester prodrugs of Fosmidomycin and its acetyl analogue FR900098. The 3,4-dichlorobenzyl substituted derivative of Fosmidomycin proved to be about twice as active as the respective Fosmidomycin prodrug, however, less active than the corresponding FR900098 prodrug. Electron donating substituents as well as voluminous substituents led to a significant reduction of activity.

Antimalarials↗
PubMed2005

Plasmodium falciparum: interaction of shikimate analogues with antimalarial drugs.

The shikimate pathway for aromatic biosynthesis presents a target for antimalarial drug development as this pathway is absent from animals. This study extends previous work on inhibitors of the shikimate pathway, by examining their interaction with the antimalarial drugs pyrimethamine and atovaquone. Combinations of atovaquone with several shikimate analogues exhibited synergistic effects. These findings highlight potential use of shikimate pathway inhibitors in combination therapy.

Animals↗
PubMed2006

Practical HPLC methods for the quantitative determination of common antimalarials in Africa.

This article describes high-performance liquid chromatographic assays for the quantification of sulfadoxine (SDX), pyrimethamine (PYM), chloroquine (CQ), amodiaquine (AQ) and desethylamodiaquine (AQM) from whole blood. All four assays were set up and validated in Malawi using a common high-performance liquid chromatography platform and column and involved the use of simple mobile phase and extraction reagents. Calibration curves were linear (r(2)>0.95) in the ranges 5-100microg/ml, 50-1000, 150-1500, 100-1000 and 100-1000ng/ml for SDX, PYM, CQ, AQ and AQM, respectively. Intra-assay and inter-assay coefficients of variation were <15% at 3 points spanning the concentration range and <20% at the lower limit of quantification. The assays were specific with no interference from the other antimalarials described in this report. All four assays use liquid-liquid extraction, reversed-phase chromatography and UV detection and require between 50 and 200microl of blood. Because the assays share common instruments and reagents, they are cost-efficient and could be used to optimise antimalarial drug therapies in other resource poor settings.

Africa↗
PubMed2003

Antimalarial activity of Sida acuta Burm. f. (Malvaceae) and Pterocarpus erinaceus Poir. (Fabaceae).

Among strategies to combat malaria, the search for new antimalarial drugs appears to be a priority. Sheering for new antimalarial activities, four plants of the traditional medicine of Burkina Faso: Combretum micranthum, Khaya senegalensis, Pterocarpus erinaceus and Sida acuta, were tested in vitro on fresh clinical isolates of Plasmodium falciparum. The screening showed that Sida acuta has a significant activity (IC50 < 5 microg/ml), and Pterocarpus erinaceus has a moderate activity (5 microg/ml < IC50 < 50 microg/ml). Further chemical screening showed that the activity of the most active plant, Sida acuta, was related to its alkaloid contents.

Animals↗
PubMed2004

A search for natural bioactive compounds in Bolivia through a multidisciplinary approach. Part VI. Evaluation of the antimalarial activity of plants used by Isoceño-Guaraní Indians.

Seventy-seven plant extracts (corresponding to 62 different species) traditionally used by the Isoceño-Guaraní, a native community living in the Bolivian Chaco, were screened for antimalarial activity in vitro on Plasmodium falciparum chloroquine sensitive strain (F32), and on ferriprotoporphyrin (FP) IX biocrystallisation inhibition test (FBIT). Among these extracts, seven displayed strong in vitro antimalarial activity, and 25 were active in the FBIT test. Positive results on both tests were recorded for six extracts: Argemone subfusiformis aerial part, Aspidosperma quebracho-blanco bark, Castela coccinea leaves and bark, Solanum argentinum leaves and Vallesia glabra bark. Results are discussed in relation with Isoceño-Guaraní traditional medicine. Further studies to be undertaken in relation with these results are also highlighted.

Animals↗
PubMed2006

Validation of use of a traditional antimalarial remedy from French Guiana, Zanthoxylum rhoifolium Lam.

Zanthoxylum rhoifolium bark (Rutaceae) is a medicinal plant, traditionally used in French Guiana to treat and prevent malaria. Bioassay-guided extractions of Zanthoxylum rhoifolium bark have shown that antiplasmodial activity is concentrated in the alkaloid fraction. Further fractionation of this extract has yielded seven benzophenanthridine alkaloids, dihydroavicine 1, dihydronitidine 2, oxyavicine 3, oxynitidine 4, fagaridine 5, avicine 6 and nitidine 7. Antimalarial activity of the last five compounds has been evaluated, and nitidine was the most potent, displaying an IC(50)<0.27microM against Plasmodium falciparum. Investigation of the traditional remedy, a trunk bark decoction in water, has shown that fagaridine 5, avicine 6 and nitidine 7 are also present in the decoction, therefore justifying the traditional use of Zanthoxylumrhoifolium bark as antimalarial.

Animals↗
PubMed2006

Simalikalactone D is responsible for the antimalarial properties of an Amazonian traditional remedy made with Quassia amara L. (Simaroubaceae).

French Guiana (North-East Amazonia) records high malaria incidence rates. The traditional antimalarial remedy most widespread there is a simple tea made out from Quassia amara L. leaves (Simaroubaceae). This herbal tea displays an excellent antimalarial activity both in vitro and in vivo. A known quassinoid, simalikalactone D (SkD), was identified as the active compound, with an IC(50) value of 10nM against FcB1 Plasmodium falciparum chloroquine resistant strain in vitro. Lastly, it inhibits 50% of Plasmodium yoelii yoelii rodent malaria parasite at 3.7 mg/kg/day in vivo by oral route. These findings confirm the traditional use of this herbal tea.

Animals↗
PubMed2005

Quantum chemical analysis of alternative pathways for iron activation step for artemisinin, a new antimalarial drug.

Malaria is a mosquito-borne parasitic infection. It can be said that malaria is a very important tropical mosquito-borne infectious disease. The selection of antimalarial drugs depends on the species and the reported resistance pattern in each setting. Artemisinins are a new group of antimalarial drugs against the drug-resistant strains of malarial parasites. The mechanism of action of artemisinin compounds consists of two important steps: (a) activation and (b) alkylation. In the activation step by iron, there are two possible pathways for developing C-4 free radical: (a) 1.5 H-shift and (b) C-C cleavage. Here, the author performs a quantum chemical analysis of the activation reaction of artemisinin by the two alternative pathways. According to this study, the required energy for compound formation in C-C cleavage is more than that for C-O cleavage. It can be noted that the C-C cleavage pathway is less preferable, implying that the 1.5 H-shift should be the more common phenomenon.

Antimalarials↗
PubMed2004

Effects of solvent composition and ionic strength on the interaction of quinoline antimalarials with ferriprotoporphyrin IX.

Enthalpy-entropy compensation in the interaction of quinoline antimalarials with ferriprotoporphyrin IX (Fe(III)PPIX) in 40% aqueous dimethyl sulfoxide (DMSO) has been compared with that in pure aqueous solution. The data indicate that the degree of desolvation and loss of conformational freedom is virtually identical in both systems. Taken together with previous findings showing that the molar free energies of association of these drugs with Fe(III)PPIX in both solvent systems are very similar, this suggests that the recognition site on the metalloporphyrin is comparable in both cases. This is despite the fact that Fe(III)PPIX exists as a dimer in aqueous solution, but is monomeric in 40% DMSO. Free energies of association of chloroquine, quinine and quinidine with Fe(III)PPIX are largely insensitive to the concentration of sodium perchlorate in 40% DMSO. This demonstrates that electrostatic interactions play only a minor role in the overall stability of these complexes under these conditions. Increasing DMSO concentration greatly weakens the interactions of chloroquine, amodiaquine, quinine, quinidine and 9-epiquinine with Fe(III)PPIX. This suggests that hydrophobic interaction plays a major role in the stability of these complexes. Further investigation of chloroquine has revealed that the free energy of association with Fe(III)PPIX also weakens as a function of decreasing solvent polarity in pure organic solvents. However, the free energies of association are weaker in the mixed aqueous solvent than in pure organic solvents. This indicates that dispersion and electrostatic interactions are relatively strong in the non-aqueous environment. The results demonstrate that any successful model of antimalarial drug-Fe(III)PPIX interactions will need to take both solvation and electrostatic factors into account.

Animals↗
PubMed2005

Interactions of quinoline antimalarials with hematin in solution.

Quinoline antimalarial drugs such as chloroquine and related compounds are believed to act by targeting ferriprotoporphyrin IX (Fe(III)PPIX) in the form of hematin (H(2)O/HO-Fe(III)PPIX), its mu-oxo dimer ([Fe(III)PPIX](2)O) or crystalline beta-hematin ([Fe(III)PPIX](2)) in the malaria parasite. Fe(III)PPIX is formed when the parasite digests host hemoglobin during its intraerythrocytic blood stage. This has led to a number of studies on the interaction of Fe(III)PPIX with quinoline antimalarials and related compounds. This article reviews the spectroscopy, thermodynamics and structures of Fe(III)PPIX-quinoline complexes in solution.

Antimalarials↗
PubMed2006

Development and validation of a reversed-phase LC method for analysing potentially counterfeit antimalarial medicines.

Pharmaceutical counterfeiting is more and more a public health problem, especially in developing countries where the most counterfeit drugs are antibiotics, antimalarials and other life-saving drugs. The evaluation of the phenomenon extent is of great concern to the World Health Organization for carrying out a global strategy to combat the phenomenon. To this purpose, a reversed-phase liquid chromatographic method to perform the separation and simultaneous determination of three different kinds of antimalarial drugs (chloroquine, quinine and mefloquine) was developed. The method was validated by using both commercial and in-laboratory produced tablets and was then verified on various in-laboratory produced formulations differing in excipient composition. Finally, the method was successfully applied to the analysis of medicinal samples purchased from the informal market in Congo, Burundi and Angola.

Antimalarials↗
PubMed2004

Antimalarial xanthones from Calophyllum caledonicum and Garcinia vieillardii.

The antimalarial activity of 22 xanthones against chloroquino-resistant strains of Plasmodium falciparum was evaluated. Natural caloxanthone C (1), demethylcalabaxanthone (2), calothwaitesixanthone (3), calozeyloxanthone (4), dombakinaxanthone (5), macluraxanthone (6), and 6-deoxy-gamma-mangostin (7) were isolated from Calophyllum caledonicum. 1,6-dihydroxyxanthone (8), pancixanthone A (9), isocudraniaxanthone B (10), isocudraniaxanthone A (11), 2-deprenylrheediaxanthone B (12) and 1,4,5-trihydroxyxanthone (13) were isolated from Garcinia vieillardii. Moreover, synthetic compounds (14-22) are analogues or intermediates of xanthones purified from Calophyllum caledonicum (Oger J.M., Morel C., Helesbeux J.J., Litaudon M., Seraphin D., Dartiguelongue C., Larcher G., Richomme P., Duval O. 2003. First 2-Hydroxy-3-Methylbut-3-Enyl substituted xanthones isolated from Plants: structure elucidation, synthesis and antifungal activity. Natural Product Research 17(3), 195-199; Helesbeux J.J., Duval O., Dartiguelongue C., Seraphin D., Oger J.M., Richomme P., 2004. Synthesis of 2-hydroxy-3-methylbut-3-enyl substituted coumarins and xanthones as natural products. Application of the Schenck ene reaction of singlet oxygen with ortho-prenylphenol precursors. Tetrahedron 60(10), 2293-2300). The relationship between antimalarial activity and molecular structure of xanthones has also been explored. The most potent xanthones (2), (3) and (7) (IC50 = c.a. 1.0 microg/mL) are 1,3,7 trioxygenated and prenylated on the positions 2 and 8.

Animals↗
PubMed2005

Cellular and molecular actions of dinitroaniline and phosphorothioamidate herbicides on Plasmodium falciparum: tubulin as a specific antimalarial target.

Microtubules play important roles in cell division, motility and structural integrity of malarial parasites. Some microtubule inhibitors disrupt parasite development at very low concentrations, but most of them also kill mammalian cells. However, the dinitroaniline family of herbicides, which bind specifically to plant tubulin, have inhibitory activity on plant cells but are relatively non-toxic to human cells. Certain dinitroanilines are also inhibitory to various protozoal parasites including Plasmodium. Here we demonstrate that the dinitroanilines trifluralin and oryzalin inhibited progression of erythrocytic Plasmodium falciparum through schizogony, blocked mitotic division, and caused accumulation of abnormal microtubular structures. Moreover, radiolabelled trifluralin interacted with purified, recombinant parasite tubulins but to a much lesser extent with bovine tubulins. The phosphorothioamidate herbicide amiprophos-methyl, which has the same herbicidal mechanism as dinitroanilines, also had antimalarial activity and a similar action on schizogony. These data suggest that P. falciparum tubulin contains a dinitroaniline/phosphorothioamidate-binding site that is not conserved in humans and might be a target for new antimalarial drugs.

Aniline Compounds↗
PubMed2004

Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents.

Chloroquine resistance in Plasmodium falciparum is primarily conferred by mutations in pfcrt. Parasites resistant to chloroquine can display hypersensitivity to other antimalarials; however, the patterns of crossresistance are complex, and the genetic basis has remained elusive. We show that stepwise selection for resistance to amantadine or halofantrine produced previously unknown pfcrt mutations (including S163R), which were associated with a loss of verapamil-reversible chloroquine resistance. This was accompanied by restoration of efficient chloroquine binding to hematin in these selected lines. This S163R mutation provides insight into a mechanism by which PfCRT could gate the transport of protonated chloroquine through the digestive vacuole membrane. Evidence for the presence of this mutation in a Southeast Asian isolate supports the argument for a broad role for PfCRT in determining levels of susceptibility to structurally diverse antimalarials.

Alanine↗