scholarly journals Ribofuranose as a carrier of tetraoxane and 4-aminoquinoline antimalarial pharmacophores

2008 ◽  
Vol 73 (11) ◽  
pp. 1021-1025 ◽  
Author(s):  
Igor Opsenica ◽  
Kirsten Smith ◽  
Lucia Gerena ◽  
Sandra Gaica ◽  
Bogdan Solaja
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Multidrug Resistant ◽  
Carrier Molecule

Several tetraoxane and 4-aminoquinoline molecules were prepared in order to examine the influence of ribofuranose as a carrier molecule on the antimalarial activity of test compounds. The synthesized compounds showed pronounced antimalarial activity against Plasmodium falciparum chloroquine susceptible D6, chloroquine resistant W2 and multidrug-resistant TM91C235 (Thailand) strains. The aminoquinoline derivative 4 was more active against W2 and TM91C235 strains than the control compounds (CQ and MFQ).

scholarly journals Phenylpropanoids and Furanocoumarins as Antibacterial and Antimalarial Constituents of the Bhutanese Medicinal Plant Pleurospermum amabile

2014 ◽  
Vol 9 (7) ◽  
pp. 1934578X1400900
Author(s):  
Phurpa Wangchuk ◽  
Stephen G. Pyne ◽  
Paul A. Keller ◽  
Malai Taweechotipatr ◽  
Sumalee Kamchonwongpaisan
Keyword(s):  
Antibacterial Activity ◽  
Plasmodium Falciparum ◽  
Bacillus Subtilis ◽  
Medicinal Plant ◽  
Antimalarial Activity ◽  
Biological Activities ◽  
Multidrug Resistant ◽  
Scientific Data ◽  
Methyl Eugenol ◽  
Weak Antibacterial Activity

With the objective of determining safety and verifying the traditional uses of the Bhutanese medicinal plant, Pleurospermum amabile Craib & W. W. Smith, we investigated its crude extracts and the isolated phytochemicals for their biological activities. Four phenylpropanoids [( E)-isomyristicin (1), ( E)-isoapiol (2), methyl eugenol (3) and ( E)-isoelemicin (4)] and six furanocoumarins [psoralen (5), bergapten (6), isoimperatorin (7), isopimpinellin (8), oxypeucedanin hydrate (9) and oxypeucedanin methanolate (10)] were isolated from this plant. Among the test samples, compound 10 showed weak antibacterial activity against Bacillus subtilis and best antimalarial activity against the Plasmodium falciparum strains, TM4/8.2 (chloroquine and antifolate sensitive) and K1CB1 (multidrug resistant). None of the test samples showed cytotoxicity. This study generated scientific data that support the traditional medical uses of the plant.

scholarly journals Plasmodium falciparum-Based Bioassay for Measurement of Artemisinin Derivatives in Plasma or Serum

2004 ◽  
Vol 48 (3) ◽  
pp. 954-960 ◽  
Author(s):  
Paktiya Teja-Isavadharm ◽  
James O. Peggins ◽  
Thomas G. Brewer ◽  
Nicholas J. White ◽  
H. Kyle Webster ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
High Performance ◽  
Antimalarial Activity ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Response Curves ◽  
Artemisinin Derivatives ◽  
Treatment Regimens ◽  
Limit Of Quantitation

ABSTRACT Artemisinin and its derivatives, artesunate and artemether, are rapidly acting antimalarials that are used for the treatment of severe and uncomplicated multidrug-resistant falciparum malaria. To optimize treatment regimens that use this new class of antimalarials, there is a need for readily available and reproducible assays to monitor drug levels closely in patients. A sensitive and reproducible bioassay for the measurement of the concentrations of artemisinin derivatives in plasma and serum is described. By modifying the in vitro drug susceptibility test, it was found that antimalarial activity in plasma or serum containing an unknown concentration of drug could be equated to the known concentrations of dihydroartemisinin (DHA) required to inhibit parasite growth. Dose-response curves for a Plasmodium falciparum clone (clone W2) and DHA were used as a standard for each assay. Assays with plasma or serum spiked with DHA proved to be reproducible (coefficient of variation, ≤10.9%), with a lower limit of quantitation equivalent to 2.5 ng of DHA per ml. For plasma spiked with artesunate or artemether, there was good agreement of the results obtained by the bioassay and the concentrations measured by high-performance liquid chromatography (HPLC) with electrochemical detection. The bioassay for measurement of the antimalarial activities of artemisinin derivatives in body fluids requires a smaller volume of plasma or serum and is more sensitive than the presently available HPLC methods, can provide pharmacodynamic parameters for determination of activity against the parasite, and should enhance the design of more appropriate dosage regimens for artemisinin drugs.

scholarly journals ComparativeEx VivoActivity of Novel Endoperoxides in Multidrug-Resistant Plasmodium falciparum and P. vivax

2012 ◽  
Vol 56 (10) ◽  
pp. 5258-5263 ◽  
Author(s):  
Jutta Marfurt ◽  
Ferryanto Chalfein ◽  
Pak Prayoga ◽  
Frans Wabiser ◽  
Grennady Wirjanata ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Ex Vivo ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Intrinsic Activity ◽  
Drug Resistant ◽  
The Novel ◽  
Content Type ◽  
Artemisinin Derivatives

ABSTRACTThe declining efficacy of artemisinin derivatives againstPlasmodium falciparumhighlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against bothP. falciparumandP. vivaxmalaria, comparativeex vivoantimalarial activity againstPlasmodiumisolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP).Ex vivodrug susceptibility was assessed in 46 field isolates (25P. falciparumand 21P. vivax). The novel endoperoxide compounds exhibited potentex vivoactivity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC50s) in both species (median IC50s between 1.9 and 3.6 nM inP. falciparumand 0.7 and 4.6 nM inP. vivax). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the twoPlasmodiumspecies: whereas theirex vivoactivity correlated positively with CQ, PIP, AS, and DHA inP. falciparum, the same was not apparent inP. vivax. The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistantP. vivax. The high activity against drug-resistant strains of bothPlasmodiumspecies confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity.

scholarly journals On peroxide antimalarials

2007 ◽  
Vol 72 (12) ◽  
pp. 1181-1190 ◽  
Author(s):  
Igor Opsenica ◽  
Dejan Opsenica ◽  
Milka Jadranin ◽  
Kirsten Smith ◽  
Wilbur Milhous ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Natural Product ◽  
Antimalarial Activity ◽  
Multidrug Resistant ◽  
Activity Relationship ◽  
Similar Activity ◽  
Structure Activity ◽  
Relationship Of ◽  
Insight Into ◽  
Better Than

Several dicyclohexylidene tetraoxanes were prepared in order to gain a further insight into structure-activity relationship of this kind of antimalarials. The tetraoxanes 2-5, obtained as a cis/trans mixture, showed pronounced antimalarial activity against Plasmodium falciparum chloroquine susceptible D6, chloroquine resistant W2 and multidrug-resistant TM91C235 (Thailand) strains. They have better than or similar activity to the corresponding desmethyl dicyclohexylidene derivatives. Two chimeric endoperoxides with superior antimalarial activity to the natural product ascaridole were also synthesized.

scholarly journals Multi-omic Characterization of the Mode of Action of a Potent New Antimalarial Compound, JPC-3210, Against Plasmodium falciparum

2019 ◽  
Vol 19 (2) ◽  
pp. 308-325 ◽  
Author(s):  
Geoffrey W. Birrell ◽  
Matthew P. Challis ◽  
Amanda De Paoli ◽  
Dovile Anderson ◽  
Shane M. Devine ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Mode Of Action ◽  
Antimalarial Activity ◽  
Protein Translation ◽  
Multidrug Resistant ◽  
Metabolomics Data ◽  
The Impact ◽  
Hemoglobin Metabolism

The increasing incidence of antimalarial drug resistance to the first-line artemisinin combination therapies underpins an urgent need for new antimalarial drugs, ideally with a novel mode of action. The recently developed 2-aminomethylphenol, JPC-3210, (MMV 892646) is an erythrocytic schizonticide with potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity, potent in vivo efficacy against murine malaria, and favorable preclinical pharmacokinetics including a lengthy plasma elimination half-life. To investigate the impact of JPC-3210 on biochemical pathways within P. falciparum-infected red blood cells, we have applied a “multi-omics” workflow based on high resolution orbitrap mass spectrometry combined with biochemical approaches. Metabolomics, peptidomics and hemoglobin fractionation analyses revealed a perturbation in hemoglobin metabolism following JPC-3210 exposure. The metabolomics data demonstrated a specific depletion of short hemoglobin-derived peptides, peptidomics analysis revealed a depletion of longer hemoglobin-derived peptides, and the hemoglobin fractionation assay demonstrated decreases in hemoglobin, heme and hemozoin levels. To further elucidate the mechanism responsible for inhibition of hemoglobin metabolism, we used in vitro β-hematin polymerization assays and showed JPC-3210 to be an intermediate inhibitor of β-hematin polymerization, about 10-fold less potent then the quinoline antimalarials, such as chloroquine and mefloquine. Further, quantitative proteomics analysis showed that JPC-3210 treatment results in a distinct proteomic signature compared with other known antimalarials. While JPC-3210 clustered closely with mefloquine in the metabolomics and proteomics analyses, a key differentiating signature for JPC-3210 was the significant enrichment of parasite proteins involved in regulation of translation. These studies revealed that the mode of action for JPC-3210 involves inhibition of the hemoglobin digestion pathway and elevation of regulators of protein translation. Importantly, JPC-3210 demonstrated rapid parasite killing kinetics compared with other quinolones, suggesting that JPC-3210 warrants further investigation as a potentially long acting partner drug for malaria treatment.

scholarly journals Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase

2016 ◽  
Vol 60 (8) ◽  
pp. 4886-4895 ◽  
Author(s):  
Ebere Sonoiki ◽  
Andres Palencia ◽  
Denghui Guo ◽  
Vida Ahyong ◽  
Chen Dong ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Multidrug Resistant ◽  
Trna Synthetase ◽  
Mechanisms Of Action ◽  
Unnatural Amino Acid ◽  
Leucine Incorporation ◽  
Wild Type ◽  
Content Type ◽  
Editing Domain

ABSTRACTThere is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles againstPlasmodium falciparum. Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain)P. falciparum(50% inhibitory concentration [IC50] of 310 nM and 490 nM, respectively) and efficacy against murinePlasmodium bergheiinfection when administered orally once daily for 4 days (90% effective dose [ED90], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding aP. falciparumleucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of theP. falciparumLeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [14C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain ofP. falciparumLeuRS.

scholarly journals In vitro evaluation of erythromycin in chloroquine resistant brazilian P. falciparum freshly isolates: modulating effect and antimalarial activity evidence

1999 ◽  
Vol 41 (4) ◽  
pp. 249-253 ◽  
Author(s):  
Carla M. S. MENEZES ◽  
Karin KIRCHGATTER ◽  
Sílvia M. F. DI SANTI ◽  
Carine SAVALLI ◽  
Fabíola G. MONTEIRO ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimicrobial Therapy ◽  
Antimalarial Activity ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Chloroquine Resistance ◽  
Reversal Agent ◽  
Resistance Modulation ◽  
Erythromycin A

Erythromycin, a reversal agent in multidrug-resistant cancer, was assayed in chloroquine resistance modulation. The in vitro microtechnique for drug susceptibility was employed using two freshly isolates of Plasmodium falciparum from North of Brazil. The antimalarial effect of the drug was confirmed, with an IC50 estimates near the usual antimicrobial therapy concentration, and a significant statistical modulating action was observed for one isolate.

scholarly journals Optimization of Xanthones for Antimalarial Activity: the 3,6-Bis-ω-Diethylaminoalkoxyxanthone Series

2002 ◽  
Vol 46 (1) ◽  
pp. 144-150 ◽  
Author(s):  
Jane Xu Kelly ◽  
Rolf Winter ◽  
David H. Peyton ◽  
David J. Hinrichs ◽  
Michael Riscoe
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Multidrug Resistant ◽  
Food Vacuole ◽  
Ionic Interactions ◽  
Side Chains ◽  
Antimalarial Agents ◽  
Unique Manner

ABSTRACT Hydroxyxanthones have been identified as novel antimalarial agents. The compounds are believed to exert their activity by complexation to heme and inhibition of hemozoin formation. Modification of the xanthone structure was pursued to improve their antimalarial activity. Attachment of R-groups bearing protonatable nitrogen atoms was conducted to enhance heme affinity through ionic interactions with the propionate side chains of the metalloporphyrin and to facilitate drug accumulation in the parasite food vacuole. A series of 3,6-bis-ω-diethylaminoalkoxyxanthones with side chains ranging from 2 to 8 carbon atoms were prepared and evaluated. Measurement of heme affinity for each of the derivatives revealed a strong correlation (R 2 = 0.97) between affinity and antimalarial potency. The two most active compounds in the series contained 5- and 6-carbon side chains and exhibited low nanomolar 50% inhibitory concentration (IC50) values against strains of chloroquine-susceptible and multidrug-resistant Plasmodium falciparum in vitro. Both of these xanthones exhibit stronger heme affinity (8.26 × 105 and 9.02 × 105 M−1, respectively) than either chloroquine or quinine under similar conditions and appear to complex heme in a unique manner.

scholarly journals A small-molecule inhibitor of the DNA recombinase Rad51 from Plasmodium falciparum synergizes with the antimalarial drugs artemisinin and chloroquine

2019 ◽  
Vol 294 (20) ◽  
pp. 8171-8183 ◽  
Author(s):  
Pratap Vydyam ◽  
Dibyendu Dutta ◽  
Niranjan Sutram ◽  
Sunanda Bhattacharyya ◽  
Mrinal Kanti Bhattacharyya
Keyword(s):  
Plasmodium Falciparum ◽  
Tertiary Structure ◽  
Antimalarial Activity ◽  
Specific Inhibitor ◽  
Multidrug Resistant ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Dna Damaging Agents ◽  
Mammalian Cell Lines ◽  
Molecule Inhibitor

Malaria parasites repair DNA double-strand breaks (DSBs) primarily through homologous recombination (HR). Here, because the unrepaired DSBs lead to the death of the unicellular parasite Plasmodium falciparum, we investigated its recombinase, PfRad51, as a potential drug target. Undertaking an in silico screening approach, we identified a compound, B02, that docks to the predicted tertiary structure of PfRad51 with high affinity. B02 inhibited a drug-sensitive P. falciparum strain (3D7) and multidrug-resistant parasite (Dd2) in culture, with IC50 values of 8 and 3 μm, respectively. We found that B02 is more potent against these P. falciparum strains than against mammalian cell lines. Our findings also revealed that the antimalarial activity of B02 synergizes with those of two first-line malaria drugs, artemisinin (ART) and chloroquine (CQ), lowering the IC50 values of ART and CQ by 15- and 8-fold, respectively. Our results also provide mechanistic insights into the anti-parasitic activity of B02, indicating that it blocks the ATPase and strand-exchange activities of PfRad51 and abrogates the formation of PfRad51 foci on damaged DNA at chromosomal sites, probably by blocking homomeric interactions of PfRad51 proteins. The B02-mediated PfRad51 disruption led to the accumulation of unrepaired parasitic DNA and rendered parasites more sensitive to DNA-damaging agents, including ART. Our findings provide a rationale for targeting the Plasmodium DSB repair pathway in combination with ART. We propose that identification of a specific inhibitor of HR in Plasmodium may enable investigations of HR's role in Plasmodium biology, including generation of antigenic diversity.

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