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PubMed1991

A new phloroglucinol derivative from Hypericum calycinum with antifungal and in vitro antimalarial activity.

The new phloroglucinol derivative 1 has been isolated from the light petroleum ether extract of the aerial parts of Hypericum calycinum. Its structure has been established by means of 1H- and 13C-NMR spectroscopy and by nOe, MHQC, and HMBC experiments on its monomethyl ether derivative 3. Compound 1 was fungicidal against Cladosporium cucumerinum in a TLC bioassay. In addition, this new phloroglucinol derivative was also found to exert an interesting antimalarial activity in an in vitro test system.

Animals↗

PubMed1999

Antimalarials from Stephania venosa, Prismatomeris sessiliflora, Diospyros montana and Murraya siamensis.

Fourteen compounds isolated from Stephania venosa, Prismatomeris sessiliflora, Diospyros montana and Murraya siamensis were tested for their antimalarial potential. The 6a,7-dehydroaporphine alkaloids dehydrostephanine and dehydrocrebanine showed potent activity with IC50 values of 40 and 70 ng/ml, respectively. The 13C-NMR data of rubiadin, rubiadin-1-methyl ether, diospyrin and 5-hydroxy-4-methoxy-2-naphthal-dehyde were extensively studied.

Antimalarials↗

PubMed1990

Antimalarial activity of Tanzanian medicinal plants.

Tanzanian medicinal plants were extracted and tested for in vitro antimalarial activity, using the multidrug resistant K1 strain of Plasmodium falciparum. Of 49 plants investigated, extracts of three plants were found to have an IC50 between 5-10 micrograms/ml, extracts of 18 other plants showed an IC50 between 10 and 50 micrograms/ml, all others were less active. The three most active extracts were obtained from the tubers of Cyperus rotundus L. (Cyperaceae), the rootbark of Hoslundia opposita Vahl. (Labiatae), and the rootbark of Lantana camara L. (Verbenaceae).

Animals↗

PubMed2006

Return of chloroquine antimalarial efficacy in Malawi.

BACKGROUND: In 1993, Malawi became the first country in Africa to replace chloroquine with the combination of sulfadoxine and pyrimethamine for the treatment of malaria. At that time, the clinical efficacy of chloroquine was less than 50%. The molecular marker of chloroquine-resistant falciparum malaria subsequently declined in prevalence and was undetectable by 2001, suggesting that chloroquine might once again be effective in Malawi. METHODS: We conducted a randomized clinical trial involving 210 children with uncomplicated Plasmodium falciparum malaria in Blantyre, Malawi. The children were treated with either chloroquine or sulfadoxine\#8211;pyrimethamine and followed for 28 days to assess the antimalarial efficacy of the drug. RESULTS: In analyses conducted according to the study protocol, treatment failure occurred in 1 of 80 participants assigned to chloroquine, as compared with 71 of 87 participants assigned to sulfadoxine\#8211;pyrimethamine. The cumulative efficacy of chloroquine was 99% (95% confidence interval [CI], 93 to 100), and the efficacy of sulfadoxine\#8211;pyrimethamine was 21% (95% CI, 13 to 30). Among children treated with chloroquine, the mean time to parasite clearance was 2.6 days (95% CI, 2.5 to 2.8) and the mean time to the resolution of fever was 10.3 hours (95% CI, 8.1 to 12.6). No unexpected adverse events related to the study drugs occurred. CONCLUSIONS: Chloroquine is again an efficacious treatment for malaria, 12 years after it was withdrawn from use in Malawi. (ClinicalTrials.gov number, NCT00125489 [ClinicalTrials.gov].).

Animals↗

PubMed1993

Cloning, sequence determination, and regulation of the ribonucleotide reductase subunits from Plasmodium falciparum: a target for antimalarial therapy.

Malaria remains a leading cause of morbidity and mortality worldwide, accounting for more than one million deaths annually. We have focused on the reduction of ribonucleotides to 2'-deoxyribonucleotides, catalyzed by ribonucleotide reductase, which represents the rate-determining step in DNA replication as a target for antimalarial agents. We report the full-length DNA sequence corresponding to the large (PfR1) and small (PfR2) subunits of Plasmodium falciparum ribonucleotide reductase. The small subunit (PfR2) contains the major catalytic motif consisting of a tyrosyl radical and a dinuclear Fe site. Whereas PfR2 shares 59% amino acid identity with human R2, a striking sequence divergence between human R2 and PfR2 at the C terminus may provide a selective target for inhibition of the malarial enzyme. A synthetic oligopeptide corresponding to the C-terminal 7 residues of PfR2 inhibits mammalian ribonucleotide reductase at concentrations approximately 10-fold higher than that predicted to inhibit malarial R2. The gene encoding the large subunit (PfR1) contains a single intron. The cysteines thought to be involved in the reduction mechanism are conserved. In contrast to mammalian ribonucleotide reductase, the genes for PfR1 and PfR2 are located on the same chromosome and the accumulation of mRNAs for the two subunits follow different temporal patterns during the cell cycle.

Amino Acid Sequence↗

PubMed1996

The pfmdr1 gene of Plasmodium falciparum confers cellular resistance to antimalarial drugs in yeast cells.

The exact role of the pfmdr1 gene in the emergence of drug resistance in the malarial parasite Plasmodium falciparum remains controversial. pfmdr1 is a member of the ATP binding cassette (ABC) superfamily of transporters that includes the mammalian P-glycoprotein family. We have introduced wild-type and mutant variants of the pfmdr1 gene in the yeast Saccharomyces cerevisiae and have analyzed the effect of pfmdr1 expression on cellular resistance to quinoline-containing antimalarial drugs. Yeast transformants expressing either wild-type or a mutant variant of mouse P-glycoprotein were also analyzed. Dose-response studies showed that expression of wild-type pfmdr1 causes cellular resistance to quinine, quinacrine, mefloquine, and halofantrine in yeast cells. Using quinacrine as substrate, we observed that increased resistance to this drug in pfmdr1 transformants was associated with decreased cellular accumulation and a concomitant increase in drug release from preloaded cells. The introduction of amino acid polymorphisms in TM11 of Pgh-1 (pfmdr1 product) associated with drug resistance in certain field isolates of P. falciparum abolished the capacity of this protein to confer drug resistance. Thus, these findings suggest that Pgh-1 may act as a drug transporter in a manner similar to mammalian P-glycoprotein and that sequence variants associated with drug-resistance pfmdr1 alleles behave as loss of function mutations.

ATP-Binding Cassette Transporters↗

PubMed1996

On the molecular mechanism of chloroquine's antimalarial action.

Chloroquine is thought to exert its antimalarial effect by preventing the polymerization of toxic heme released during proteolysis of hemoglobin in the Plasmodium digestive vacuole. The mechanism of this blockade has not been established. We incubated cultured parasites with subinhibitory doses of [3H]chloroquine and [3H] quinidine. These [3H]quinoline compounds became associated with hemozoin as assessed by electron microscope autoradiography and subcellular fractionation. In vitro, binding of [3H]quinoline inhibitors to the hemozoin chain depended on the addition of heme substrate. These data counter previous conclusions regarding the lack of quinoline association with hemozoin, explain the exaggerated accumulation of quinolines in the plasmodium digestive vacuole, and suggest that a quinoline heme complex incorporates into the growing polymer to terminate chain extension, blocking further sequestration of toxic heme.

Animals↗

PubMed1998

The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin.

Artemisinin and its derivatives are important new antimalarial drugs. When Plasmodium falciparum-infected erythrocytes are incubated with [10-3H]dihydroartemisinin, several malaria-specific proteins become labeled. One of these proteins is the P. falciparum translationally controlled tumor protein (TCTP) homolog. In vitro, dihydroartemisinin reacts covalently with recombinant TCTP in the presence of hemin. The association between drug and protein increases with increasing drug concentration, plateauing at approximately 1 drug/TCTP molecule. By Scatchard analysis, there appear to be 2 hemin binding sites on TCTP with dissociation constants of approximately 18 microM. When the single cysteine moiety is blocked by pretreatment with iodoacetamide, hemin binding is not affected, whereas drug binding is reduced by two-thirds. Thus, TCTP reacts with artemisinin in situ and in vitro in the presence of hemin and appears to bind to hemin. The function of the malarial TCTP and the role of this reaction in the mechanism of action of artemisinin await elucidation.

Amino Acid Sequence↗

PubMed2005

Overexpression of leucyl aminopeptidase in Plasmodium falciparum parasites. Target for the antimalarial activity of bestatin.

Malaria aminopeptidases are important in the generation and regulation of free amino acids that are used in protein anabolism and for maintaining osmotic stability within the infected erythrocyte. The intraerythrocytic development of malaria parasites is blocked when the activity of aminopeptidases is specifically inhibited by reagents such as bestatin. One of the major aminopeptidases of malaria parasites is a leucyl aminopeptidase of the M17 family. We reasoned that, when this enzyme was the target of bestatin inhibition, its overexpression in malaria cells would lead to a reduced sensitivity to the inhibitor. To address this supposition, transgenic Plasmodium falciparum parasites overexpressing the leucyl aminopeptidase were generated by transfection with a plasmid that housed the full-length gene. Transgenic parasites expressed a 65-kDa protein close to the predicted molecule size of 67.831 kDa for the introduced leucyl aminopeptidase, and immunofluorescence studies localized the protein to the cytosol, the location of the native enzyme. The product of the transgene was shown to be functionally active with cytosolic extracts of transgenic parasites exhibiting twice the leucyl aminopeptidase activity compared with wild-type parasites. In vitro inhibitor sensitivity assays demonstrated that the transgenic parasites were more resistant to bestatin (EC50 64 microM) compared with the parent parasites (EC50 25 microM). Overexpression of genes in malaria parasites would have general application in the identification and validation of targets for antimalarial drugs.

Animals↗

PubMed1979

Abnormal haemoglobins in the Sudan savanna of Nigeria. III. Malaria, immunoglobulins and antimalarial antibodies in sickle cell disease.

Subjects with sickle cell disease were identified in (i) a whole population sample (2742) Garki District, Kano State, Nigeria, and in (ii) the 534 infants born into the population during five years. Eleven (2.1%) newborn had Hb.SS, as was expected from gene frequency (0.146). Prevalence was maintained in the first year of life, but fell to 0.4% at one to four years and to 0.05% (one person) over the age of nine years. Antimalarial intervention for two transmission seasons was followed by an apparent but not significant decrease in Hb.SS mortality. There was one male aged about 40 years who had Hb.SC (the expected number was three). Hb.SS children were compared to normal subjects at the same age, the same village and the same survey; they had significantly less than the expected Plasmodium malariae infection (P less than 0.01) and lower than median P. falciparum densities while below five years (P less than 0.05). Over one year of age, they tended to have below average indirect fluorescent antibody (IFA) (P less than 0.01), indirect haemagglutinating antibody (IHA) (P less than 0.01) titres and number of precipitin rings (not significant) against P. falciparum antigen, and IFA against P malariae (P less than 0.01). They had above average IgM (P less than 0.05), but their IgG concentrations did not differ from normal. We conclude that (i) sickling is sufficient to protect against P. malariae in Hb.SS but not Hb.AS; (ii) sickling prevents intense P. falciparum infection in Hb.SS, as in Hb.AS; (iii) in Hb.SS, there is less antigenic stimulus and hence less antibody against P. falciparum (like Hb.AS) and P. malariae (unlike Hb.AS); (iv) although less intense, malaria is frequently fatal in Hb.SS, especially in age-group one to four years (unlike Hb.AS); (v) IgM levels are high in Hb.SS in response to frequent infections other than malaria (unlike Hb.AS).

Adolescent↗

PubMed1984

Comparison of in vitro and in vivo antimalarial activities of 9-phenanthrenecarbinols.

Analysis of the antimalarial activity of a selected series of 17 9-phenanthrenecarbinols against cultured strains of Plasmodium falciparum and against P. berghei in mice following oral administration indicated that the rankings of activities within the series were influenced by substituents on the 9-carbinol and the route of administration. Compounds with alkylamino-alkyl groups were ranked as most active by an in vitro screening system which assayed activity against chloroquine-sensitive and chloroquine-resistant strains of cultured P. falciparum by the inhibition of uptake of radiolabelled hypoxanthine. There were few differences in ranking of activities between the two strains. Although there was a significant difference between activities of an erythro- and a threo-racemate, activities of the four optical isomers of this compound were comparable. Among the series, compounds with a 2-piperidyl substituent on the 9-carbinol were ranked most active by the oral route of administration as assayed by the cure rates of mice infected with P. berghei. Correlation of these observations with previously published data on the activity of these compounds against P. falciparum in Owl monkeys and P. berghei in mice following subcutaneous administration suggested that neither species of host nor strains of parasite significantly influenced the ranking of activities of this class of compound.

Animals↗

PubMed1986

Analogues of N-benzyloxydihydrotriazines: in vitro antimalarial activity against Plasmodium falciparum.

The antimalarial activities of a series of chlorophenyloxyalkoxy and chlorophenalkoxy N-substituted diamino-dihydrotriazines were determined in vitro against three strains of Plasmodium falciparum (Malayan Camp, Vietnam Smith, FCB) with diverse levels of resistance to chloroquine, pyrimethamine, and cycloguanil. Parasite viability was assayed by the inhibition of the uptake of radiolabelled hypoxanthine. Most of the ID-50S of these compounds were less than 1.0 ng ml-1. Consistent differences in sensitivities to these compounds were observed and appeared to be strain related. The Malayan Camp was the most sensitive and Vietnam Smith was the least sensitive. These differences appeared to be related primarily to an inherent sensitivity of a particular strain to the series of analogues examined rather than to a pattern of cross-resistance to chloroquine, pyrimethamine, or cycloguanil.

Antimalarials↗

PubMed1992

The chemotherapy of rodent malaria. XLVII. Studies on pyronaridine and other Mannich base antimalarials.

The activities of Mannich base antimalarials, including pyronaridine, have been explored against drug-sensitive (Plasmodium berghei N) and chloroquine-resistant (Plasmodium yoelii NS) rodent malaria parasites in vivo. Lines of these parasites have been developed with resistance to pyronaridine, amodiaquine, or WR 228,258. The responses and patterns of cross-resistance of these lines to Mannich bases and other blood schizontocides are inconsistent. It is concluded that some Mannich bases may prove still to be of value inthe treatment of chloroquine-resistant Plasmodium falciparum infection.

Aminoquinolines↗

PubMed1998

Antimalarial activity of unsaturated putrescine derivatives.

(E)-1,4-Diaminobut-2-ene dihydrochloride 1 (unsaturated putrescine) and some N-substituted derivatives of 1 have strong antifungal activity against a variety of plant pathogens. A series of N-alkylated putrescine derivatives was synthesised and evaluated for antimalarial activity in vitro against the asexual, intraerythrocytic stages of Plasmodium falciparum. (E)-N,N,N',N'-Tetraethyl-1,4-diaminobut-2-ene dihydrochloride 3 was the most active N-alkylated putrescine tested. Enhanced in-vitro activity was evident with the N,N'-bisbenzyl derivatives 7 and 11. Useful activity in vivo was observed only when the 7-chloroisoquinolyl moiety was present, as in 12 (an unsaturated analogue of chloroquine).

Animals↗

PubMed1988

The effects of antimalarials and folate supplements on haematological indices and red cell folate levels in Gambian children.

Haematological indices and red cell folate levels (RCF) were measured during two annual surveys in a group of Gambian children aged 3 months-5 years who were participating in a trial of malaria chemoprophylaxis with Maloprim or chlorproguanil given with or without folate supplements. Chlorproguanil was given in an adult dose of 20 mg, Maloprim as one quarter or one half of the adult dose of 25 mg pyrimethamine and 100 mg dapsone. Antimalarials and folate supplements were given fortnightly. About 20% of children had low RCF levels (less than 100 ng/ml). Among children who did not receive supplementation with folate there were no significant differences in mean RCF levels between children who received Maloprim, chlorproguanil or placebo. Among children who received folate supplements, the mean RCF was significantly lower among those receiving chlorproguanil than among the controls. Mean RCF values were similar in children who received Maloprim or placebo. If chlorproguanil is used for malaria chemoprophylaxis in young children an age-related dose should be used.

Antimalarials↗

PubMed2000

Interaction of antimalarial drug quinacrine with nucleic acids of variable sequence studied by spectroscopic methods.

The interaction of antimalarial drug quinacrine (QA) with polynucleotides is studied by UV-visible absorption, fluorescence and surface-enhanced Raman spectroscopy (SERS). The polynucleotides employed for such a study were calf thymus DNA, poly(A).poly(T), poly(A).poly(U), poly(C).poly(G) and poly(dG-dC).poly(dG-dC). Absorption and fluorescence spectra of QA complexes indicate that an interaction with the biomolecule is taking place, although different interaction mechanisms are probable depending on the sequence. The SERS spectra also reflect spectral changes which depend on the polymer sequence and that can be correlated to those observed by fluorescence, with the advantage of the detailed structural information provided by this vibrational technique. QA interacts with polynucleotides through its diprotonated form and by ring stacking. The strength of such interaction is extremely sequence dependent, thus suggesting different interaction mechanisms in each case. The SERS technique allows the simultaneous study of those polynucleotide moieties that are directly involved in the interaction thanks to the short-range character of the SERS spectroscopy. The interaction of QA with the above nucleic acids lead to a different change in the chain stability and flexibility which is further related to the different denaturation tendency of the polymer in the presence of the metal surface.

Animals↗

PubMed2003

In vivo antimalarial activity of Vernonia amygdalina.

Extracts from the leaves and root bark of Vernonia amygdalina are assessed for antimalarial activity against drug-sensitive Plasmodium berghei in mice. A standard inoculum of 1 x 10(7) infected erythrocytes is used, and leaf and root-bark extracts of 500 mg/kg, 250 mg/kg or 125 mg/kg are used in a four-day suppression test and a Rane test of established infection. Leaf extract produced 67% suppression of parasitaemia in the four-day test, while root-bark extract produced 53.5% suppression. These results are significant when compared to a placebo (P<0.001).

Animals↗

PubMedDate not supplied

Pharmacokinetics of the antimalarial drug, AQ-13, in rats and cynomolgus macaques.

The purpose of this study was to evaluate the bioavailability and pharmacokinetics of a new antimalarial drug, AQ-13, a structural analog of chloroquine (CQ) that is active against CQ-resistant Plasmodium species, in rats and cynomolgus macaques. Sprague-Dawley rats (n = 4/sex) were administered a single dose of AQ-13 intravenously (i.v.) (10 mg/kg) or orally (20 or 102 mg/kg). Blood and plasma samples were collected at several timepoints. AQ-13 achieved C(max) after oral administration at approximately 3 to 4 h and could be detected in blood for 2 to 5 days after oral administration. The ratio of area under the curve (AUC) values at the high and low dose for AQ-13 deviated from an expected ratio of 5.0, indicating nonlinear kinetics. A metabolite peak was noted in the chromatograms that was identified as monodesethyl AQ-13. Oral bioavailability of AQ-13 was good, approximately 70%. The pharmacokinetics of AQ-13 was also determined in cynomolgus macaques after single (i.v., 10 mg/kg; oral, 20 or 100 mg/kg) and multiple doses (oral loading dose of 50, 100, or 200 mg/kg on first day followed by oral maintenance dose of 25, 50, or 100 mg/kg, respectively, for 6 days). The AUC and C(max) values following single oral dose administration were not dose proportional; the C(max) value for AQ-13 was 15-fold higher following an oral dose of 100 mg/kg compared to 20 mg/kg. Monodesethyl AQ-13 was a significant metabolite formed by cynomolgus macaques and the corresponding C(max) values for this metabolite increased only 3.8-fold over the dose range, suggesting that the formation of monodesethyl AQ-13 is saturable in this species. The bioavailability of AQ-13 in cynomolgus macaques following oral administration was 23.8% for the 20-mg/kg group and 47.6% for the 100-mg/kg group. Following repeat dose administration, high concentrations of monodesethyl AQ-13 were observed in the blood by day 4, exceeding the AQ-13 blood concentrations through day 22. Saturation of metabolic pathways and reduced metabolite elimination after higher doses are suggested to play a key role in AQ-13 pharmacokinetics in macaques. In summary, the pharmacokinetic profile and metabolism of AQ-13 are very similar to that reported in the literature for chloroquine, suggesting that this new agent is a promising candidate for further development for the treatment of chloroquine-resistant malaria.

Administration, Oral↗