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 New 4-aminoquinolines as moderate inhibitors of P. falciparum malaria

2021 ◽  
pp. 5-5
Author(s):  
Igor Opsenica ◽  
Milica Selakovic ◽  
Miklos Tot ◽  
Tatjana Verbic ◽  
Jelena Srbljanovic ◽  
...  
Keyword(s):  
Mouse Model ◽  
Red Blood Cells ◽  
Falciparum Malaria ◽  
Blood Cells ◽  
Antimalarial Activity ◽  
Resistant Clone ◽  
Susceptible Clone

Synthesis of novel aminoquinoline derivatives has been accomplished and their activity against malaria strains has been examined. The compounds showed moderate in vitro antimalarial activity against two P. falciparum strains, 3D7 (CQ susceptible clone) and Dd2 (CQ resistant clone). Three amino-quinolines were further examined for antimalarial efficacy in a mouse model using a modified Thompson test. In this model, mice were infected with P. berghei-infected red blood cells, and drugs were administered orally. Anti-malarial 3 was found toxic at a dose of 320 (mg/kg)/day in 3/6 mice, however, 2/6 mice of the same group survived through day 31, and one of them was cured.

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 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

scholarly journals Synthesis, antimalarial activity evaluation and molecular docking studies of some novel dispiro-1,2,4,5-tetraoxanes

2015 ◽  
Vol 10 (4) ◽  
pp. 917 ◽  
Author(s):  
Mukesh Kumar Kumawat ◽  
Dipak Chetia
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Docking ◽  
Resistant Strain ◽  
Antimalarial Activity ◽  
Binding Pocket ◽  
Docking Studies ◽  
Spectroscopic Techniques ◽  
Molecular Docking Studies ◽  
Activity Screening

<p class="Abstract">Seven novel dispiro-1,2,4,5-tetraoxane derivatives were synthesized and characterized by a number of analytical and spectroscopic techniques. The molecules were subsequently screened for in vitro antimalarial activity against chloroquine resistant strain of <em>Plasmodium falciparum</em> (RKL-9). At antimalarial activity screening, two compounds, namely 5d (MIC = 15.6 µg/mL or 64.5 µM) and 5f (MIC = 15.6 µg/mL or 54.6 µM) were found to be about 1.5 times more potent against chloroquine resistant strain-RKL-9 compared to chloroquine (MIC = 25.0 µg/mL or 78.3 µM). Molecular docking studies of potent ligands were also performed in cysteine protease binding pocket residues of falcipain-2 as a target protein.</p><p> </p>

scholarly journals Overexpression of Plasmodium falciparum M1 Aminopeptidase Promotes an Increase in Intracellular Proteolysis and Modifies the Asexual Erythrocytic Cycle Development

Pathogens ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1452
Author(s):  
Carolina C. Hoff ◽  
Mauro F. Azevedo ◽  
Adriana B. Thurler ◽  
Sarah El Chamy Maluf ◽  
Pollyana M. S. Melo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Fold Increase ◽  
Cysteine Proteases ◽  
Aminopeptidase Activity ◽  
Lower Sensitivity ◽  
Wild Type ◽  
Erythrocytic Cycle ◽  
Transgenic Parasite

Plasmodium falciparum, the most virulent of the human malaria parasite, is responsible for high mortality rates worldwide. We studied the M1 alanyl-aminopeptidase of this protozoan (PfA-M1), which is involved in the final stages of hemoglobin cleavage, an essential process for parasite survival. Aiming to help in the rational development of drugs against this target, we developed a new strain of P. falciparum overexpressing PfA-M1 without the signal peptide (overPfA-M1). The overPfA-M1 parasites showed a 2.5-fold increase in proteolytic activity toward the fluorogenic substrate alanyl-7-amido-4-methylcoumarin, in relation to the wild-type group. Inhibition studies showed that overPfA-M1 presented a lower sensitivity against the metalloaminopeptidase inhibitor bestatin and to other recombinant PfA-M1 inhibitors, in comparison with the wild-type strain, indicating that PfA-M1 is a target for the in vitro antimalarial activity of these compounds. Moreover, overPfA-M1 parasites present a decreased in vitro growth, showing a reduced number of merozoites per schizont, and also a decrease in the iRBC area occupied by the parasite in trophozoite and schizont forms when compared to the controls. Interestingly, the transgenic parasite displays an increase in the aminopeptidase activity toward Met-, Ala-, Leu- and Arg-7-amido-4-methylcoumarin. We also investigated the potential role of calmodulin and cysteine proteases in PfA-M1 activity. Taken together, our data show that the overexpression of PfA-M1 in the parasite cytosol can be a suitable tool for the screening of antimalarials in specific high-throughput assays and may be used for the identification of intracellular molecular partners that modulate their activity in P. falciparum.

scholarly journals Antimalarial activity of betulinic acid and derivatives in vitro against Plasmodium falciparum and in vivo in P. berghei-infected mice

2009 ◽  
Vol 105 (1) ◽  
pp. 275-279 ◽  
Author(s):  
Matheus Santos de Sá ◽  
José Fernando Oliveira Costa ◽  
Antoniana Ursine Krettli ◽  
Mariano Gustavo Zalis ◽  
Gabriela Lemos de Azevedo Maia ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Betulinic Acid ◽  
Antimalarial Activity

scholarly journals The effect of N-alkyl modification on the antimalarial activity of 3- hydroxypyridin-4-one oral iron chelators

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 637-643 ◽  
Author(s):  
C Hershko ◽  
EN Theanacho ◽  
DT Spira ◽  
HH Peter ◽  
P Dobbin ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Iron Chelators ◽  
Lipid Solubility ◽  
Lipophilic Compounds ◽  
Labile Iron Pool ◽  
Ring Nitrogen ◽  
Iron Pool ◽  
Chelating Compounds

Abstract The antimalaria effect of iron chelators is attributed to their interaction with a labile iron pool within parasitised erythrocytes, and it was postulated that increased affinity to iron as well as increased lipophilicity may improve antimalarial activity. In the present study we have examined the antimalarial effect of 3- hydroxypyridin-4-ones, a family of bidentate orally effective iron chelators whose lipophilicity may be modified by altering the length of the R2 substituent on the ring nitrogen. A significant dose-related suppression of Plasmodium falciparum cultures was observed with all drugs tested in vitro at concentrations of 5 mumol/L or higher. In contrast, there was a clear segregation of the in vivo effect on P berghei in rats (300 mg/kg/d subcutaneous) into two categories: compounds CP20, 38, and 40 failed to suppress malaria, whereas CP51, 94, and 96 had a strong antimalarial effect, similar or better than deferoxamine. There was a close linear correlation between the suppression of peak parasite counts and the reduction in hepatic nonheme iron induced by the various drugs tested (r = .9837). The most lipophilic compounds were also the most effective in suppressing malaria and in depleting hepatic iron stores. These data indicate that 3-hydroxypyrydin-4-ones are able to suppress malaria in vivo and in vitro. Because lipid solubility is an important determinant of antimalarial action, our study provides useful information regarding the selection of orally effective iron-chelating compounds that may be suitable for clinical application as antimalarial agents.

scholarly journals Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Letícia Tiburcio Ferreira ◽  
Juliana Rodrigues ◽  
Gustavo Capatti Cassiano ◽  
Tatyana Almeida Tavella ◽  
Kaira Cristina Peralis Tomaz ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
In Silico ◽  
Antimalarial Activity ◽  
Drug Repositioning ◽  
Dna Gyrase ◽  
Plasmodium Yoelii ◽  
Computer Assisted ◽  
Content Type

ABSTRACT Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii. Transmission-blocking activity was observed for epirubicin in vitro and in vivo. Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.

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