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PubMedDate not supplied

Innate resistance to new antimalarial drugs in Plasmodium falciparum from Nigeria.

The rapid dissemination of chloroquine-resistant Plasmodium falciparum in West Africa has been well documented and represents a significant health threat to autochthonous populations. The methodical development of alternative chemotherapeutic agents demands that dispensing new antimalarial drugs (mefloquine, halofantrine, and artemisinine [qinghaosu]) be closely monitored in order to protect their clinical utility. Indeed, mefloquine-resistant strains of P. falciparum have been reported. We present data from experiments in vitro on the innate resistance of P. falciparum isolates to mefloquine as well as a disturbing observation of transient resistance to artemisinine. The implications for the extended efficacy of these new antimalarial drugs are addressed.

Animals↗
PubMed1986

Monoclonal antibodies to lipophilic and short-sized haptens: application to the 4-amino-quinoline antimalarial drugs.

Monoclonal antibodies recognizing the 4-amino-7-chloro-quinoline (ACQ) structure, which represents the backbone of the 4-amino-quinoline antimalarial drugs, were obtained in mice, after injection of ACQ coupled to hemocyanin via the glutaraldehyde method. The resulting antibodies show a definite specificity to this hapten, but react better with compounds substituted on the exocyclic amino group in 4. It is postulated that the quinoline ring is not sufficient for the reaction with the antibodies, and that an enlarged structure, which is given by the bridge used to link hapten and carrier, entails an important increase (1000-fold) in the apparent affinity. The striking similarities between this bridge and the lateral chains of the antimalarial drugs are accountable for this enhanced recognition. This result allows us to indicate that in some instances, the bridge-structure of the immunogen should be positively involved in the epitope. This observation may become useful in the conception of immunogens, aiming to obtain antibodies directed against some lipophilic and small-sized haptens.

Aminoquinolines↗
PubMed1990

Metabolism of antimalarial sesquiterpene lactones.

Metabolism of artemisinin derivatives, which are antimalarial sesquiterpenes, appeared to lead to the production of the more polar metabolites in general. Presence of the endoperoxide moiety in the A/B ring structure seems crucial for the expression of antimalarial activity of these compounds. Microbial models served as effective predictors for the mammalian metabolism of artemisinin derivatives as well as producing quantities of metabolites for reference standards and structure elucidation studies. Combination of 2D-NMR and Thermospray HPLC/MS techniques was very useful for the structure elucidation of metabolites.

Animals↗
PubMed1994

Effects of antimalarials and protease inhibitors on plasmodial hemozoin production.

Malarial hemozoin may play an important role as a target for antimalarial drugs and in disease pathogenesis. A new assay for hemozoin was developed in which the hemozoin was separated from cells by filtration. Trophozoites have substantially more hemozoin than rings, but there are relatively small differences between chloroquine-sensitive and chloroquine-resistant strains. The effects of hemozoin content of chloroquine and artemisinin, two antimalarial drugs, and E64 and Pepstatin A, two protease inhibitors, were measured. At concentrations at which hypoxanthine incorporation was unaffected, the hemozoin content of rings was decreased by E64, but not by the other three compounds. Artemisinin and Pepstatin A also had little effect on the hemozoin content of trophozoites. Chloroquine and E64 inhibited trophozoite hemozoin formation, but inhibited hypoxanthine uptake to a similar or greater extent. When either rings or trophozoites were exposed to several higher concentrations of chloroquine, hemozoin content was diminished, but significantly less than hypoxanthine uptake. Various concentrations of E64, in contrast, inhibited hemozoin production by both rings and trophozoites significantly more than hypoxanthine incorporation, suggesting that hemozoin production may be directly affected by E64.

Animals↗
PubMed1994

Non-sequence-specific antimalarial activity of oligodeoxynucleotides.

The effects of exogenously applied oligodeoxynucleotides on Plasmodium falciparum proliferation was investigated. A fluorescence-activated cell sorter assay was employed to measure parasitemia after administration of either phosphodiester or phosphorothioate oligodeoxynucleotides. We report sequence-independent antimalarial activity preferentially with phosphorothioate congeners with IC50 values in the 1-2 microM range. Phosphorothioate oligodeoxynucleotides which were antisense, sense or nonsense to Plasmodium mRNA, as well as homopolymers (30-mers containing all A or T bases) were equally effective inhibitors of parasitemia. The antimalarial activity was dependent upon oligomer length, concentration, and time of addition to the cultures but was independent of the parasite strain tested. Four P. falciparum strains, including a multi-drug-resistant strain (MDR-K), a drug-sensitive strain (FCR-3), a erythrocyte membrane sialic acid-independent strain (7G8) and a strain isolated from a cerebral malaria patient (CM-87) were equally susceptible to treatment with a phosphorothioate oligomer. Inhibition of red cell invasion is primarily responsible for the observed decrease in proliferation as determined by a study of parasite maturation in the presence of a 30-mer nonsense phosphorothioate oligodeoxynucleotide.

Animals↗
PubMed1996

Recombinant Plasmodium falciparum dihydrofolate reductase-based in vitro screen for antifolate antimalarials.

We describe the system for screening the effective antifolate antimalarials that uses the recombinant Plasmodium falciparum DHFR domain of the bifunctional DHFR-TS expressed in Escherichia coli, and were designed with amino acid alterations found in the DHFR genes of the antifolate resistant strains. The validity of the screen was verified by the subsequent examination of several substituted pyrrolo[2,3-d]pyrimidines for their antimalarial activity. Among the 120 chemical derivatives, 5 compounds were identified by their preferential inhibition of the drug sensitive pfDHFR to that of the mammalian isoenzyme. As compared to the sensitive enzyme, the decrease in response of the cycolguanil-resistant and pyrimethamine-resistant enzymes to the selected compounds were relatively moderate. This gave folds decrease in sensitivity of 0.8-7.5 and 3.6-29, respectively, while those for cycloguanil and pyrimethamine were 400 and 308. The compounds inhibited the growth of drug-sensitive cultured P. falciparum with 50% effective concentrations of the ranged 0.17-30 nM. As contrasted with the sensitive strain, the fold decrease in sensitivity of the resistant parasites were 0.9-2 and 15-50 in the case of the test compounds, while those for cycloguanil and pyrimethamine were 690 and 20,500. Moreover, the most selective pyrrolo-pyrimidine (P-1) showed in vivo activity against P. berghei in mice.

Animals↗
PubMed1995

Molecular modeling studies of the artemisinin (qinghaosu)-hemin interaction: docking between the antimalarial agent and its putative receptor.

Artemisinin (qinghaosu, QHS) is a promising new antimalarial agent that is effective against drug-resistant strains of malaria. The antimalarial activity of this drug appears to be mediated by an interaction of the drug's endoperoxide bridge with intraparasitic hemin. We have carried out a computer-assisted docking of QHS with hemin from various starting configurations and found that, in the most stable docked configuration, the endoperoxide bridge is in close proximity to the hemin iron. In contrast, an inactive analog, deoxyartemisinin (DQHS), docks in a different manner. Further computer analysis of the drug-hemin interaction might aid in the design of new QHS congeners.

Antimalarials↗
PubMed1995

Quantification of the individual enantiomer plasma concentrations of the candidate antimalarial agent N4-[2,6-dimethoxy-4-methyl-5-[(3-trifluoromethyl)phenoxy]-8-quinolinyl] - 1,4-pentanediamine (WR 238,605).

A high-performance liquid chromatographic method was developed to quantitate the plasma concentrations of the individual enantiomers of a candidate 8-aminoquinoline antimalarial agent WR 238,605 (I). The method employed one-step liquid extraction of a 0.5-ml plasma sample followed by direct injection of the extract through a chiral column and detection by fluorescence. Quantification was achieved using an internal standard. The limit of quantification was 10 ng/ml for each enantiomer. The method is sufficiently sensitive to quantitate the plasma concentrations of both enantiomers for 30 days following a single oral dose of 400 mg of the antimalarial agent administered as the racemic succinate salt to healthy human male volunteers. In nearly all samples taken 12 h to 30 days post-dose from three subjects, the difference in the plasma concentrations of the two enantiomers is less than 10%.

Adolescent↗
PubMed1988

Screening for antimalarial activity in the genus Potomorphe.

Ethanolic extracts (CEE) of leaves from Potomorphe umbellata and Potomorphe peltata, popularly said to have antimalarial capacity, were submitted to the 4-day suppressive test in Plasmodium berghei-infected mice. The CEE of P. umbellata administered either orally (250 and 1250 mg/kg) or subcutaneously (100 and 500 mg/kg) evidenced strong antimalarial activity, significantly reducing the levels of parasitaemia in a dose-dependent manner. On the other hand, the CEE of P. peltata was ineffective in lowering the parasitemic levels in malarious mice, which had been treated either orally (500 mg/kg) or subcutaneously (20, 100 and 500 mg/kg). An ethanol extract of the dry whole plant of P. peltata was also inactive.

Animals↗
PubMed1991

Antimalarial activity and cytotoxicity of Evodia fatraina stem bark extracts.

Stem bark extracts of Evodia fatraina (Rutaceae) were tested for antimalarial activity in vitro on Plasmodium falciparum using an isotopic semi-microtest and in vivo on Plasmodium berghei in mice. Ethyl acetate extract showed moderate antimalarial activity in vitro (IC50 = 8.5 micrograms ml-1). However, ethanolic extract exhibited significant potency in vivo (65% suppression of parasitaemia). Moreover, low toxicity against HeLa cells and L 929 fibroblasts was observed with ethanolic extract (IC50 = 95 micrograms ml-1 and 60 micrograms ml-1, respectively).

Administration, Oral↗
PubMed1992

Evaluation of the in vitro antimalarial activity of Picralima nitida extracts.

Extracts of Picralima nitida seeds, fruit rind, and stem bark have been investigated in vitro for antimalarial activity. The extracts showed remarkable inhibitory activity against drug resistant clones of Plasmodium falciparum at doses of 1.23-32 micrograms/ml. The dichloromethane extract of the fruit rind was the most active of the crude extracts, with IC50 values of 1.61 micrograms/ml for the Indochina (W-2), clone and 2.41 micrograms/ml for the Sierra Leone (D-6), clone. An alkaloid fraction obtained from the methanol extract of the stem bark gave an IC50 value of 2.00 micrograms/ml and 1.23 micrograms/ml in the W-2 and D-6 clones, respectively. The result supports the continued ethnomedical exploration of the plant as a potential antimalarial drug.

Animals↗
PubMed1994

Antimalarial activity of cedronin.

Cedronin was isolated from Simaba cedron Planchon (Simaroubaceae), a species popularly believed in South America to have antimalarial properties. It was examined for in vitro and in vivo antimalarial activities and for cytotoxicity against KB cells. Experimental results showed that cedronin was active against chloroquine-sensitive and resistant strain, with an IC50 of 0.25 micrograms/ml (0.65 mumol/ml). It was also found to be active in vivo against Plasmodium vinkei with an IC50 of 1.8 mg/kg (4.7 nM/kg) in the classic 4-day test. Cedronin belongs to the small group of quassinoids with a C19 basic skeleton and shows a rather low cytotoxicity against KB cells (IC50 = 4 micrograms/ml, 10.4 microM) as compared with C20 biologically active quassinoids; however its toxic/therapeutic ratio (10/1.8) remains lower than chloroquine (10/0.5).

Animals↗
PubMedDate not supplied

Multidrug assay method for antimalarials.

A general separation strategy, involving solid-phase extraction followed by reversed-phase ion-pairing HPLC with an organic counter ion for a set of 11 widely used antimalarial drugs and metabolites has been developed. The basis underlying the separation has been explored and work, including quantitative data, has been carried out on illustrative separations which form the basis of novel quantitative assays of groups of antimalarials which are relevant to current prophylaxis and treatment of malaria.

Antimalarials↗
PubMedDate not supplied

Analysis of basic antimalarial drugs by CZE and MEKC. Part 1--Critical factors affecting separation.

The separations of 11 antimalarial drugs and metabolites are shown by CZE at low pH and by MEKC at high pH. CZE is shown to be superior to MEKC in resolution capability for these compounds under the conditions examined. Both are shown to provide different selectivities to those obtained by ion-pair reversed-phase HPLC. The effect of sample injection solvent is examined in CZE and it is shown that field-amplified sample injection is effective for these compounds. In addition, it is shown that injection of sample in an organic solvent such as methanol augments the stacking of analytes resulting in lower detection limits. The limit of detection of some antimalarials in a urine matrix is reported.

Antimalarials↗
PubMed1994

Photoreactivity of biologically active compounds. VII. Interaction of antimalarial drugs with melanin in vitro as part of phototoxicity screening.

The drugs commonly used in the treatment of malaria are photochemically unstable. Several of these compounds accumulate in melanin-rich tissues and cause toxic reactions which may be light induced. As part of the screening of the photochemical properties and phototoxic capabilities of antimalarials, the in vitro interaction of eight antimalarials with melanin was studied. The dissociation constant for the drug-melanin complex and the relative number of binding sites on melanin were estimated for six of the drugs using a curve-fitting program. The reaction rate for the formation of the melanin-drug complex was determined, and the complexes were further characterized by zeta potential measurements.

Antimalarials↗
PubMed2005

A colorimetric high-throughput beta-hematin inhibition screening assay for use in the search for antimalarial compounds.

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.

Animals↗
PubMed2004

Cytotoxic and antimalarial constituents from the roots of Eurycoma longifolia.

Sixty-five compounds were isolated from the roots of Eurycoma longifolia and characterized by comprehensive analyses of their 1D and 2D NMR, and mass spectral data. Among these isolates, four quassinoid diterpenoids were reported from natural sources for the first time, namely eurycomalide A (1), eurycomalide B (2), 13beta, 21-dihydroxyeurycomanol (3), and 5alpha, 14beta, 15beta-trihydroxyklaineanone (4). Screening of cytotoxicity, anti-HIV and antimalarial activity of these isolated compounds was also furnished by in vitro assays. Compounds 12, 13, 17, 18, 36, 38, 59, and 62 demonstrated strong cytotoxicity toward human lung cancer (A-549) cell lines, however, 12, 13, 17, 38, 57, 58, and 59 exhibited strong cytoxicity toward human breast cancer (MCF-7) cell lines. Compounds 57 and 58 displayed potent antimalarial activity against the resistant Plasmodium falciparum. The thorough studies on the stereochemistry of the different quassinoid diterpenoids provide a clear reference to the scientists who are interested on this field.

Animals↗
PubMed2005

Carbonic anhydrase inhibitors. Inhibition of Plasmodium falciparum carbonic anhydrase with aromatic sulfonamides: towards antimalarials with a novel mechanism of action?

The malarial parasite Plasmodium falciparum encodes for an alpha-carbonic anhydrase (CA) enzyme possessing catalytic properties distinct of that of the human host, which was only recently purified. A series of aromatic sulfonamides, most of which were Schiff's bases derived from sulfanilamide/homosulfanilamide/4-aminoethylbenzenesulfonamide and substituted-aromatic aldehydes, or ureido-substituted such sulfonamides, were investigated for in vitro inhibition of the malarial parasite enzyme (pfCA) and the growth of P. falciparum. Several inhibitors with affinity in the micromolar range (K(I)'s in the range of 0.080-1.230 microM) were detected, whereas the most potent such derivatives were the clinically used sulfonamide CA inhibitor acetazolamide, and 4-(3,4-dichlorophenyl-ureidoethyl)-benzenesulfonamide, which showed an inhibition constant of 80 nM against pfCA, being four times more effective an inhibitor as compared to acetazolamide (K(I) of 315 nM). The lipophilic 4-(3,4-dichlorophenylureido-ethyl)-benzenesulfonamide was also an effective in vitro inhibitor for the growth of P. falciparum (IC50 of 2 microM), whereas acetazolamide achieved the same level of inhibition at 20 microM. This is the first study proving that antimalarials possessing a novel mechanism of action can be obtained, by inhibiting a critical enzyme for the life cycle of the parasite. Indeed, by inhibiting pfCA, the synthesis of pyrimidines mediated by carbamoylphosphate synthase is impaired in P. falciparum but not in the human host. Sulfonamide CA inhibitors have the potential for the development of novel antimalarial drugs.

Animals↗