scholarly journals In Vitro Antimalarial Activity of a New Organometallic Analog, Ferrocene-Chloroquine

1998 ◽  
Vol 42 (3) ◽  
pp. 540-544 ◽  
Author(s):  
O. Domarle ◽  
G. Blampain ◽  
H. Agnaniet ◽  
T. Nzadiyabi ◽  
J. Lebibi ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Tartaric Acid ◽  
Antimalarial Activity ◽  
Chloroquine Resistance ◽  
Highly Effective ◽  
Human Therapy ◽  
Potential Use

ABSTRACT The in vitro activities of new organometallic chloroquine analogs, based on 4-amino-quinoleine compounds bound to a molecule of ferrocene, were evaluated against chloroquine-susceptible, chloroquine-intermediate, and chloroquine-resistant, culture-adaptedPlasmodium falciparum lineages by a proliferation test. One of the ferrocene analogs totally restored the activity of chloroquine against chloroquine-resistant parasites. This compound, associated with tartaric acid for better solubility, was highly effective. The role of the ferrocene in reversing chloroquine resistance is discussed, as is its potential use for human therapy.

scholarly journals Role of the Neurotransmitter Reuptake-Blocking Activity of Antidepressants in Reversing Chloroquine Resistance In Vitro in Plasmodium falciparum

2000 ◽  
Vol 44 (10) ◽  
pp. 2689-2692 ◽  
Author(s):  
Dale Taylor ◽  
Jason C. Walden ◽  
Ashley H. Robins ◽  
Peter J. Smith
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Chloroquine Resistance ◽  
Resistant Isolate ◽  
Significant Shift ◽  
Sensitive Clone ◽  
Resistance Reversal ◽  
Synaptic Level

ABSTRACT Since the discovery of the chloroquine (CQ) resistance reversal properties of several different, structurally unrelated classes of compounds, including antidepressants, the way is again open to employ the aminoquinoline drugs to combat malaria effectively. In this study, CQ sensitivity was restored to varying extents in vitro in the CQ-resistant Plasmodium falciparum strain RSA11 by using the antidepressants amitriptyline, citalopram, oxaprotiline, and nomifensine. The 50% inhibitory concentrations (IC50) of CQ were reduced from 360 to as low as 11 nM when antidepressants were present. These particular antidepressants are highly specific for blocking the ATP-binding cassette transport protein-mediated reuptake of different neurotransmitters at the synaptic level. This study was aimed at determining the extent to which the neurotransmitter reuptake-blocking properties of these antidepressants play a role in the reversal process. None of the compounds or CQ-antidepressant combinations tested had innate antimalarial activity. No chemosensitizer or combination showed an increased CQ accumulation or significant shift in the IC50 in the CQ-sensitive clone D10. Of the compounds tested, citalopram, a highly specific serotonin reuptake blocker, produced the largest shift observed in the IC50 for the resistant isolate RSA11. No particular class of antidepressant was found to be better than any other at restoring CQ sensitivity. We conclude that the resistance-reversing properties of these compounds do not correlate with their activities as reuptake blockers.

scholarly journals Saquinavir Inhibits the Malaria Parasite's Chloroquine Resistance Transporter

2012 ◽  
Vol 56 (5) ◽  
pp. 2283-2289 ◽  
Author(s):  
Rowena E. Martin ◽  
Alice S. Butterworth ◽  
Donald L. Gardiner ◽  
Kiaran Kirk ◽  
James S. McCarthy ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Heterologous Expression ◽  
Protease Inhibitors ◽  
Chloroquine Resistance ◽  
Content Type ◽  
Chloroquine Resistance Transporter ◽  
Resistant Phenotype ◽  
Transgenic Parasites

ABSTRACTThe antiretroviral protease inhibitors (APIs) ritonavir, saquinavir, and lopinavir, used to treat HIV infection, inhibit the growth ofPlasmodium falciparumat clinically relevant concentrations. Moreover, it has been reported that these APIs potentiate the activity of chloroquine (CQ) against this parasitein vitro. The mechanism underlying this effect is not understood, but the degree of chemosensitization varies between the different APIs and, with the exception of ritonavir, appears to be dependent on the parasite exhibiting a CQ-resistant phenotype. Here we report a study of the role of theP. falciparumchloroquine resistance transporter (PfCRT) in the interaction between CQ and APIs, using transgenic parasites expressing different PfCRT alleles and using theXenopus laevisoocyte system for the heterologous expression of PfCRT. Our data demonstrate that saquinavir behaves as a CQ resistance reverser and that this explains, at least in part, its ability to enhance the effects of CQ in CQ-resistantP. falciparumparasites.

scholarly journals Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids

2012 ◽  
Vol 56 (10) ◽  
pp. 5356-5364 ◽  
Author(s):  
Carol E. Griffin ◽  
Jonathan M. Hoke ◽  
Upeka Samarakoon ◽  
Junhui Duan ◽  
Jianbing Mu ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Cinchona Alkaloids ◽  
Chloroquine Resistance ◽  
Digestive Vacuole ◽  
Content Type ◽  
Chloroquine Resistance Transporter ◽  
Clonal Lines

ABSTRACTTheCinchonaalkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (−)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (−)-isomersin vitroandin vivoagainstPlasmodium falciparummalaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparumchloroquine resistance transporter), reversed the normal potency order of quinine and quinidine towardP. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured thein vitrosusceptibility of eight clonal lines ofP. falciparumderived from the 106/1 strain, each containing a uniquepfcrtallele, to fourCinchonastereoisomer pairs: quinine and quinidine; cinchonidine and cinchonine; hydroquinine and hydroquinidine; 9-epiquinine and 9-epiquinidine. Stereospecific potency of theCinchonaalkaloids was associated with changes in charge and hydrophobicity of mutable PfCRT amino acids. In isogenic chloroquine-resistant lines, the IC50ratio of (−)/(+) CA pairs correlated with side chain hydrophobicity of the position 76 residue. Second-site PfCRT mutations negated the K76I stereospecific effects: charge-change mutations C72R or Q352K/R restored potency patterns similar to the parent K76 line, while V369F increased susceptibility to the alkaloids and nullified stereospecific differences between alkaloid pairs. Interactions between key residues of the PfCRT channel/transporter with (−) and (+) alkaloids are stereospecifically determined, suggesting that PfCRT binding plays an important role in the antimalarial activity of quinine and otherCinchonaalkaloids.

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 Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: in vitro genotypic and phenotypic characterization

2020 ◽  
Author(s):  
Nonlawat Boonyalai ◽  
Brian A Vesely ◽  
Chatchadaporn Thamnurak ◽  
Chantida Praditpol ◽  
Watcharintorn Fagnark ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Copy Number ◽  
Antimalarial Activity ◽  
Drug Susceptibility ◽  
Drug Combinations ◽  
Chloroquine Resistance ◽  
Phenotypic Characterization ◽  
Field Isolates

Abstract Background: High rates of dihydroartemisinin-piperaquine (DHA-PPQ) treatment failures have been documented for uncomplicated Plasmodium falciparum in Cambodia. The genetic markers plasmepsin 2 (pfpm2), exonuclease (pfexo) and chloroquine resistance transporter (pfcrt) genes are associated with PPQ resistance and are used for monitoring the prevalence of drug resistance and guiding malaria drug treatment policy.Methods: To examine the relative contribution of each marker to PPQ resistance, in vitro culture and the PPQ survival assay were performed on seventeen P. falciparum isolates from northern Cambodia, and the presence of E415G-Exo and PfCRT mutations (T93S, H97Y, F145I, I218F, M343L, C350R, and G353V) as well as pfpm2 copy number polymorphisms were determined. Parasites were then cloned by limiting dilution and the cloned parasites were tested for drug susceptibility. Isobolographic analysis of several drug combinations for standard clones and newly cloned P. falciparum Cambodian isolates was also determined.Results: The characterization of culture-adapted isolates revealed that the presence of novel PfCRT mutations (T93S, H97Y, F145I, and I218F) with E415G-Exo mutation can confer PPQ-resistance, in the absence of pfpm2 amplification. In vitro testing of PPQ resistant parasites demonstrated a bimodal dose-response, the existence of a swollen digestive vacuole phenotype, and an increased susceptibility to quinine, chloroquine, mefloquine and lumefantrine . To further characterize drug sensitivity, parental parasites were cloned in which a clonal line, 14-B5, was identified as sensitive to arteminsinin and piperaquine but resistant to chloroquine. Assessment of the clone against a panel of drug combinations revealed antagonistic activity for six different drug combinations. However, mefloquine-proguanil and atovoquone-proguanil combinations revealed synergistic antimalarial activity. Conclusions: Surveillance for PPQ resistance in regions relying on DHA-PPQ as the first-line treatment is dependent on the monitoring of molecular markers of drug resistance. P. falciparum harboring novel PfCRT mutations with E415G-exo mutations displayed PPQ resistant phenotype. The presence of pfpm2 amplification was not required to render parasites PPQ resistant suggesting that the increase in pfpm2 copy number alone is not the sole modulator of PPQ resistance. Genetic background of circulating field isolates appear to play a role in drug susceptibility and biological responses induced by drug combinations. The use of latest field isolates may be necessary for assessment of relevant drug combinations against P. falciparum strains and when down-selecting novel drug candidates.

scholarly journals Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro

Blood ◽  
1990 ◽  
Vol 76 (6) ◽  
pp. 1250-1255 ◽  
Author(s):  
S Whitehead ◽  
TE Peto
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Antimalarial Activity ◽  
Clinical Malaria ◽  
Inhibitory Effect ◽  
Parasite Development ◽  
And Control ◽  
Speed Of Onset

Abstract Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

scholarly journals In vitro activities of novel catecholate siderophores against Plasmodium falciparum.

1996 ◽  
Vol 40 (9) ◽  
pp. 2094-2098 ◽  
Author(s):  
B Pradines ◽  
F Ramiandrasoa ◽  
L K Basco ◽  
L Bricard ◽  
G Kunesch ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Mechanism Of Action ◽  
Ribonucleotide Reductase ◽  
Antimalarial Activity ◽  
Iron Chelators ◽  
Resistant Clone ◽  
Iron Deprivation ◽  
Level Of Activity ◽  
Susceptible Clone

The activities of novel iron chelators, alone and in combination with chloroquine, quinine, or artemether, were evaluated in vitro against susceptible and resistant clones of Plasmodium falciparum with a semimicroassay system. N4-nonyl,N1,N8-bis(2,3-dihydroxybenzoyl) spermidine hydrobromide (compound 7) demonstrated the highest level of activity: 170 nM against a chloroquine-susceptible clone and 1 microM against a chloroquine-resistant clone (50% inhibitory concentrations). Compounds 6, 8, and 10 showed antimalarial activity with 50% inhibitory concentrations of about 1 microM. Compound 7 had no effect on the activities of chloroquine, quinine, and artemether against either clone, and compound 8 did not enhance the schizontocidal action of either chloroquine or quinine against the chloroquine-resistant clone. The incubation of compound 7 with FeCI3 suppressed or decreased the in vitro antimalarial activity of compound 7, while no effect was observed with incubation of compound 7 with CuSO4 and ZnSO4. These results suggest that iron deprivation may be the main mechanism of action of compound 7 against the malarial parasites. Chelator compounds 7 and 8 primarily affected trophozoite stages, probably by influencing the activity of ribonucleotide reductase, and thus inhibiting DNA synthesis.

scholarly journals Synthesis and in Vitro Antimalarial Activity of Alkyl Esters Gallate as a Growth Inhibitors of Plasmodium Falciparum

2018 ◽  
Vol 34 (2) ◽  
pp. 655-662 ◽  
Author(s):  
Ade Arsianti ◽  
Hendry Astuti ◽  
Fadilah Fadilah ◽  
Daniel Martin Simadibrata ◽  
Zoya Marie Adyasa ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Growth Inhibitors ◽  
Alkyl Esters
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