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PubMed1999

In vitro activities of pyronaridine, alone and in combination with other antimalarial drugs, against Plasmodium falciparum.

The in vitro activities of pyronaridine, alone and in combination with established antimalarial drugs, were assessed by isotopic microtest. Pyronaridine was highly active against all Cameroonian isolates. A positive correlation was observed between the response to pyronaridine and that to chloroquine. Drug combination studies showed synergy between pyronaridine and primaquine, additive effects with 4-aminoquinolines, and weak antagonism with dihydroartemisinin, antifolates, or amino alcohols.

Animals↗
PubMed2000

Antimalarial activities of aminooxy compounds.

Twenty-three aminooxy compounds have been examined for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum in vitro. Eight of these compounds were found to have 50% inhibitory concentrations less than 10 microM, with the best drugs being canaline (the aminooxy analogue of ornithine) and CGP51905A at 297 +/- 23.6 nM and 242 +/- 18.8 nM, respectively. Canaline was also assayed in combination with the ornithine decarboxylase inhibitor difluoromethylornithine, and the two drugs were found to be synergistic in antimalarial activity.

Aminobutyrates↗
PubMed2002

Potent in vitro antimalarial activity of metacycloprodigiosin isolated from Streptomyces spectabilis BCC 4785.

Bioassay-guided fractionation of the extract from the fermentation broth of Streptomyces spectabilis BCC 4785 led to the isolation of three principle antimalarial agents, metacycloprodigiosin, bafilomycin A(1), and spectinabilin. Metacycloprodigiosin exhibited potent in vitro activity against Plasmodium falciparum K1, with a 50% inhibitory concentration of 0.0050 +/- 0.0010 microg/ml, while its cytotoxicity was much weaker.

Animals↗
PubMed2002

Assessment of azithromycin in combination with other antimalarial drugs against Plasmodium falciparum in vitro.

Initial field malaria prophylaxis trials with azithromycin revealed insufficient efficacy against falciparum malaria to develop azithromycin as a single agent. The objective of this in vitro study was to determine the best drug combination(s) to evaluate for future malaria treatment and prophylaxis field trials. In vitro, azithromycin was tested in combination with chloroquine against 10 representative Plasmodium falciparum isolates. Azithromycin was also assessed in combination with eight additional antimalarial agents against two or three multidrug-resistant P. falciparum isolates. Parasite susceptibility testing was carried out with a modification of the semiautomated microdilution technique. The incubation period was extended from the usual 48 h to 68 h. Fifty percent inhibitory concentrations (IC(50)s) were calculated for each drug alone and for drugs in fixed combinations of their respective IC(50)s (1:1, 3:1, 1:3, 4:1, 1:4, and 5:1). These data were used to calculate fractional inhibitory concentrations and isobolograms. Chloroquine-azithromycin studies revealed a range of activity from additive to synergistic interactions for the eight chloroquine-resistant isolates tested, while an additive response was seen for the two chloroquine-sensitive isolates. Quinine, tafenoquine, and primaquine were additive to synergistic with azithromycin, while dihydroartemisinin was additive with a trend toward antagonism. The remaining interactions appeared to be additive. These results suggest that a chloroquine-azithromycin combination should be evaluated for malaria prophylaxis and that a quinine-azithromycin combination should be evaluated for malaria treatment in areas of drug resistance.

Animals↗
PubMed2003

Resistance to antimalarials in Southeast Asia and genetic polymorphisms in pfmdr1.

Resistance to antimalarial drugs is a public health problem worldwide. Molecular markers for drug-resistant malaria, such as pfcrt and pfmdr1 polymorphisms, could serve as useful surveillance tools. To evaluate this possibility, sequence polymorphisms in pfcrt (position 76) and pfmdr1 (positions 86, 184, 1034, 1042, and 1246) and in vitro drug sensitivities were measured for 65 Plasmodium falciparum isolates from Thailand, Myanmar, Vietnam, and Bangladesh. The pfcrt Thr76 polymorphism was present in 97% of samples, consistent with observations that chloroquine resistance is well established in this region. Polymorphisms in pfmdr1 clustered into four specific patterns: the wild type (category I), a Tyr86 polymorphism only (category II), a Phe184 polymorphism only (category III), and Phe184 in combination with Cys1034 and/or Asp1042 (category IV). Isolates in categories I and III were more sensitive to chloroquine and more resistant to mefloquine, artesunate, and artemisinin than isolates in categories II and IV (P </= 0.01). Mefloquine resistance was significantly more common in category I and III isolates than in category II and IV isolates, with a prevalence ratio of 14.95 (95% confidence interval, 3.88 to 57.56). These categories identified mefloquine resistance with a sensitivity and a specificity of 94 and 91%, respectively. The pfmdr1 gene copy number was measured by real-time PCR as a ratio of the amount of pfmdr1 DNA to the amount of lactate dehydrogenase (ldh) DNA. Eight samples had pfmdr1 DNA/ldh DNA ratios >/=3. The isolates in all 8 samples fell into categories I and III and were significantly more resistant to mefloquine, quinine, artemisinin, and artesunate and more sensitive to chloroquine than the isolates in the 57 samples with <3 copies of the gene (P </= 0.001). Thus, measurement of pfmdr1 mutations and gene copy number may be useful for surveillance of mefloquine-resistant malaria in Southeast Asia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Potent inhibitors of Plasmodium phospholipid metabolism with a broad spectrum of in vitro antimalarial activities.

We characterized the potent in vitro antimalarial activity and biologic assessment of 13 phospholipid polar head analogs on a comparative basis. There was a positive relationship between the abilities of the drugs to inhibit parasite growth in culture and their abilities to specifically inhibit phosphatidylcholine biosynthesis of Plasmodium falciparum-infected erythrocytes. Maximal activity of G25 was observed for the trophozoite stage of the 48-h erythrocytic cycle (50% inhibitory concentration, 0.75 nM), whereas the schizont and ring stages were 12- and 213-fold less susceptible. The compounds exerted a rapid nonreversible cytotoxic effect, with complete clearance of parasitemia after 5 h of contact with the mature stages. The compounds were highly specific against P. falciparum, with much lower toxicity against three other mammalian cell lines, and the in vitro therapeutic indices ranged from 300 to 2,500,000. Finally, the monoquaternary ammonium E10 and two bis-ammonium salts, G5 and G25, were similarly active against multiresistant strains and fresh isolates of P. falciparum. This impressive selective in vitro toxicity against P. falciparum strongly highlights the clinical potential of these quaternary ammonium salts for malarial chemotherapy.

Animals↗
PubMed2003

In vivo antimalarial activities of mono- and bis quaternary ammonium salts interfering with Plasmodium phospholipid metabolism.

We previously showed that quaternary ammonium salts have potent antimalarial activities against the blood stage of drug-resistant Plasmodium falciparum. In the present study, 13 compounds of this series were comparatively assessed in murine in vivo malarial models. Mice infected with Plasmodium berghei were successfully treated with 11 quaternary ammonium salts in a 4-day suppressive test with a once-daily intraperitoneal administration. The dose required to decrease parasitemia by 50% (ED(50)) ranged from 0.04 to 4.5 mg/kg of body weight. For six mono- and three bis-quaternary ammonium salts, the therapeutic indices (i.e., 50% lethal dose and ED(50)) were higher than 5, and at best, around 20 to 30 for five of them (E6, E8, F4, G5, and G25), which is comparable to that of chloroquine under the same conditions. Plasmodium chabaudi was significantly more susceptible to G5, G15, and G25 compounds than P. berghei. Similar therapeutic indices were obtained, regardless of the administration mode or initial parasitemia (up to 11.2%). Parasitemia clearance was complete without recrudescence. Subcutaneously administered radioactive compounds had a short elimination half-life in mice (3.5 h) with low bioavailability (17.3%), which was likely due to the permanent cationic charge of the molecule. The high in vivo therapeutic index in the P. chabaudi-infected mouse model and the absence of recrudescence highlight the enormous potential of these quaternary ammonium salts for clinical malarial treatment.

Animals↗
PubMed2004

Nonisotopic, semiautomated plasmodium falciparum bioassay for measurement of antimalarial drug levels in serum or plasma.

A simple, nonisotopic, semiautomated bioassay for the measurement of antimalarial drug levels in plasma or serum based on the quantitation of histidine-rich protein II in malaria culture is presented. The assay requires only small sample volumes and was found to be highly sensitive and reproducible. The results closely paralleled those obtained with isotopic bioassays (R = 0.988, P < 0.001) and high-performance liquid chromatography-electrochemical detection (R = 0.978, P < 0.001).

Animals↗
PubMed2004

Antimalarial quinolines and artemisinin inhibit endocytosis in Plasmodium falciparum.

Endocytosis is a fundamental process of eukaryotic cells and fulfills numerous functions, most notably, that of macromolecular nutrient uptake. Malaria parasites invade red blood cells and during their intracellular development endocytose large amounts of host cytoplasm for digestion in a specialized lysosomal compartment, the food vacuole. In the present study we have examined the effects of artemisinin and the quinoline drugs chloroquine and mefloquine on endocytosis in Plasmodium falciparum. By using novel assays we found that mefloquine and artemisinin inhibit endocytosis of macromolecular tracers by up to 85%, while the latter drug also leads to an accumulation of undigested hemoglobin in the parasite. During 5-h incubations, chloroquine inhibited hemoglobin digestion but had no other significant effect on the endocytic pathway of the parasite, as assessed by electron microscopy, the immunofluorescence localization of hemoglobin, and the distribution of fluorescent and biotinylated dextran tracers. By contrast, when chloroquine was added to late ring stage parasites, followed by a 12-h incubation, macromolecule endocytosis was inhibited by more than 40%. Moreover, there is an accumulation of transport vesicles in the parasite cytosol, possibly due to a disruption in vacuole-vesicle fusion. This fusion block is not observed with mefloquine, artemisinin, quinine, or primaquine but is mimicked by the vacuole alkalinizing agents ammonium chloride and monensin. These results are discussed in the light of present theories regarding the mechanisms of action of the antimalarials and highlight the potential use of drugs in manipulating and studying the endocytic pathway of malaria parasites.

Ammonium Chloride↗
PubMed2004

Unraveling the mode of action of the antimalarial choline analog G25 in Plasmodium falciparum and Saccharomyces cerevisiae.

Pharmacological studies have indicated that the choline analog G25 is a potent inhibitor of Plasmodium falciparum growth in vitro and in vivo. Although choline transport has been suggested to be the target of G25, the exact mode of action of this compound is not known. Here we show that, similar to its effects on P. falciparum, G25 prevents choline entry into Saccharomyces cerevisiae cells and inhibits S. cerevisiae growth. However, we show that the uptake of this compound is not mediated by the choline carrier Hnm1. An hnm1Delta yeast mutant, which lacks the only choline transporter gene HNM1, was not altered in the transport of a labeled analog of this compound. Eleven yeast mutants lacking genes involved in different steps of phospholipid biosynthesis were analyzed for their sensitivity to G25. Four mutants affected in the de novo cytidyldiphosphate-choline-dependent phosphatidylcholine biosynthetic pathway and, surprisingly, a mutant strain lacking the phosphatidylserine decarboxylase-encoding gene PSD1 (but not PSD2) were found to be highly resistant to this compound. Based on these data for S. cerevisiae, labeling studies in P. falciparum were performed to examine the effect of G25 on the biosynthetic pathways of the major phospholipids phosphatidylcholine and phosphatidylethanolamine. Labeling studies in P. falciparum and in vitro studies with recombinant P. falciparum phosphatidylserine decarboxylase further supported the inhibition of both the de novo phosphatidylcholine metabolic pathway and the synthesis of phosphatidylethanolamine from phosphatidylserine. Together, our data indicate that G25 specifically targets the pathways for synthesis of the two major phospholipids, phosphatidylcholine and phosphatidylethanolamine, to exert its antimalarial activity.

Animals↗
PubMed2004

Novel antimalarial compounds isolated in a survey of self-medicative behavior of wild chimpanzees in Uganda.

Following a veterinary and behavioral survey of chimpanzees from a natural population in Uganda, leaf samples of Trichilia rubescens were collected because of the unusual method of ingestion observed. The methanolic crude extract of T. rubescens leaves exhibited significant antimalarial activity in vitro. Bioassay-directed fractionation provided two new limonoids, trichirubines A and B. A greater understanding of the role of secondary compounds in the primate diet may be helpful in recovering naturally occurring compounds of medicinal significance for human medicine.

Animals↗
PubMed2005

Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance?

Mu et al. (Mu, J., M. T. Ferdig, X. Feng, D. A. Joy, J. Duan, T. Furuya, G. Subramanian, L. Aravind, R. A. Cooper, J. C. Wootton, M. Xiong, and X. Z. Su, Mol. Microbiol. 49:977-989, 2003) recently reported exciting associations between nine new candidate transporter genes and in vitro resistance to chloroquine (CQ) and quinine (QN), with six of these loci showing association with CQ or QN in a southeast Asian population sample. We replicated and extended this work by examining polymorphisms in these genes and in vitro resistance to eight drugs in parasites collected from the Thailand-Burma border. To minimize problems of multiple testing, we used a two-phase study design, while to minimize problems caused by population structure, we analyzed parasite isolates collected from a single clinic. We first examined associations between genotype and drug response in 108 unique single-clone parasite isolates. We found strong associations between single nucleotide polymorphisms in pfmdr and mefloquine (MFQ), artesunate (AS), and lumefantrine (LUM) response. We also observed associations between an ABC transporter (G7) and response to QN and AS and between another ABC transporter (G49) and response to dihydro-artemisinin (DHA). We reexamined significant associations in an independent sample of 199 unique single-clone infections from the same location. The significant associations with pfmdr-1042 detected in the first survey remained. However, with the exception of the G7-artesunate association, all other associations observed with the nine new candidate transporters disappeared. We also examined linkage disequilibrium (LD) between markers and phenotypic correlations between drug responses. We found minimal LD between genes. Furthermore, we found no correlation between chloroquine and quinine responses, although we did find expected strong correlations between MFQ, QN, AS, DHA, and LUM. To conclude, we found no evidence for an association between 8/9 candidate genes and response to eight different antimalarial drugs. However, the consistent association observed between a 3-bp indel in G7 and AS response merits further investigation.

ATP-Binding Cassette Transporters↗
PubMed2005

Antimalarial activity of human immunodeficiency virus type 1 protease inhibitors.

Aspartic proteases play key roles in the biology of malaria parasites and human immunodeficiency virus type 1 (HIV-1). We tested the activity of seven HIV-1 protease inhibitors against cultured Plasmodium falciparum. All compounds inhibited the development of parasites at pharmacologically relevant concentrations. The most potent compound, lopinavir, was active against parasites (50% inhibitory concentration [IC50], 0.9 to 2.1 microM) at concentrations well below those achieved by ritonavir-boosted lopinavir therapy. Lopinavir also inhibited the P. falciparum aspartic protease plasmepsin II at a similar concentration (IC50, 2.7 microM). These findings suggest that use of HIV-1 protease inhibitors may offer clinically relevant antimalarial activity.

Animals↗
PubMed2005

2,4-diaminopteridine-based compounds as precursors for de novo synthesis of antifolates: a novel class of antimalarials.

We have tested the hypothesis that 2,4-diamino-6-hydroxymethyl-pteridine (DAP), 2,4-diaminopteroic acid (DAPA), and 2,4 diamino-N10-methyl-pteroic acid (DAMPA) could be converted into aminopterin (from DAP and DAPA) and methotrexate (from DAMPA), both of which are potent inhibitors of dihydrofolate reductase, a proven drug target for Plasmodium falciparum. DAP, DAPA, and DAMPA inhibited parasite growth in the micromolar range; DAMPA was the most active, with 50% inhibitory concentrations in vitro of 446 ng/ml against the antifolate-sensitive strain and 812 ng/ml against the highly resistant strain under physiological folate conditions. DAMPA potentiates the activity of the sulfone dapsone, an inhibitor of dihydropteroate synthase, but not that of chlorcycloguanil, a known inhibitor of dihydrofolate reductase (DHFR). Experiments with a Saccharomyces cerevisiae strain dependent upon the P. falciparum DHFR enzyme showed that DHFR is a target of DAMPA in that system. We hypothesize that DAMPA is converted to methotrexate by the parasite dihydrofolate synthase, which explains the synergy of DAMPA with dapsone but not with chlorcycloguanil. This de novo synthesis will not occur in the host, since it lacks the complete folate pathway. If this hypothesis holds true, the de novo synthesis of the toxic compounds could be used as a framework for the search for novel potent antimalarial antifolates.

Animals↗
PubMed2006

Antimalarial activity of a synthetic endoperoxide (RBx-11160/OZ277) against Plasmodium falciparum isolates from Gabon.

OZ277 is a newly developed, fully synthetic endoperoxide antimalarial that we tested against field isolates from Gabon. A comparison of activities of OZ277 with artesunate, mefloquine, and chloroquine showed OZ277 to be highly active against all parasite isolates. Artesunate and mefloquine also showed potent antiparasitic activity, but all isolates were chloroquine resistant.

Animals↗
PubMed2006

New potential antimalarial agents: therapeutic-index evaluation of pyrroloquinazolinediamine and its prodrugs in a rat model of severe malaria.

Tetra-acetamide pyrroloquinazolinediamine (PQD-A4) and bis-ethylcarbamyl pyrroloquinazolinediamine (PQD-BE) are new derivatives of pyrroloquinazolinediamine (PQD) and are being investigated as potential chemotherapeutic agents for the treatment of malaria. Comparative studies to assess the therapeutic indices of PQD-A4, PQD-BE, and PQD were conducted in Plasmodium berghei-infected rats following daily intragastric dosing for three consecutive days. Artesunate (AS), a standard drug for treatment of severe malaria, was used as a comparator. The minimum doses required to clear malaria parasitemia were 156 micromol/kg of body weight for AS and 2.4 micromol/kg for PQD, PQD-4A, and PQD-BE. The maximum tolerated dose (MTD) of AS was 625 micromol/kg, and its therapeutic index was calculated to be 4. The MTDs of PQD-A4, PQD-BE, and PQD were found to be 190, 77, and 24 micromol/kg, respectively, yielding therapeutic indices of 80, 32, and 10, respectively. Although PQD-A4 and PQD-BE are only half as potent as PQD based on their curative effects, the two new derivatives, PQD-4A and PQD-BE, are 8.0-fold and 3.2-fold safer, respectively, than their parent compound when they are dosed for three consecutive days. Oral PQD-A4 and PQD-BE are 44 to 70 times more potent on an mg basis than intravenous AS. As assessed from the therapeutic index over 3 days, PQD-A4, PQD-BE, and PQD administered orally are 20.0, 8.0, and 2.5 times safer than AS given intravenously. The results indicate that PQD-4A is a promising candidate for antimalarial treatment.

Animals↗
PubMed1999

Development of a Plasmodium PCR for monitoring efficacy of antimalarial treatment.

We report in this work a highly sensitive and nonradioactive PCR method for the detection of the four species of parasite causing human malaria. Plasmodium-specific primers corresponding to the small-subunit rRNA genes of the malaria parasite were used, and a 291-bp fragment was amplified. Our results showed a high specificity for the four human Plasmodium species, and we were able to detect one parasite in 50 microl of whole blood. The responses of 12 patients infected with Plasmodium falciparum to antimalarial therapy were monitored by PCR diagnosis and examination of thick blood film for at least 20 min by an experienced microscopist. For one patient this study allowed early diagnosis of therapeutic failure, confirmed 7 days later by examination of the thick blood film. A total of 134 samples were examined; 94 were positive by PCR, and among these 68 were positive by thick blood film examination. The sensitivity of the thick blood film was 72.3% compared to PCR and 60.7% compared to dot blot hybridization.

Animals↗