scholarly journals In vitro antimalarial activity of inhibitors of the human GTPase Rac1

2021 ◽  
Author(s):  
Silvia Parapini ◽  
Silvio Paone ◽  
Emanuela Erba ◽  
Loredana Cavicchini ◽  
Manoochehr Pourshaban ◽  
...  
Keyword(s):  
Blood Cells ◽  
Antimalarial Activity ◽  
Mechanisms Of Action ◽  
Antimalarial Drugs ◽  
Parasite Growth ◽  
Selectivity Index ◽  
Effective Vaccine ◽  
Intracellular Pathogens ◽  
Parasite Invasion

Malaria accounts for millions of cases and thousands of deaths every year. In the absence of an effective vaccine, drugs are still the most important tool in the fight against the disease. Plasmodium parasites developed resistance for all the classes of known antimalarial drugs. Thus, the search for antimalarial drugs with novel mechanisms of action is compelling. The human GTPase Rac1 plays a role in parasite invasion of the host cell in many intracellular pathogens. Also in Plasmodium falciparum , it was suggested an involvement of Rac1 both during the invasion process and parasite intracellular development. Aim of this work is to test a panel of Rac1 inhibitors as potential antimalarial drugs. Fourteen commercially available or newly synthesized inhibitors of Rac1 were tested for antimalarial activity. Among these, EHop-016 was the most effective against P. falciparum in vitro, with nanomolar IC 50 (138.8 ± 16.0 nM on the chloroquine-sensitive D10 strain and 321.5 ± 28.5 nM on the chloroquine-resistant W2 strain), and Selectivity Index of 37.8. EHop-016 did not inhibit parasite invasion of red blood cells but affected parasite growth inside them. Among the tested Rac1 inhibitors, EHop-016 showed a promising activity that raises attention on this class of molecules as potential antimalarials and deserves further investigation.

From classical antimalarial drugs to new compounds based on the mechanism of action of artemisinin

2001 ◽  
Vol 73 (7) ◽  
pp. 1173-1188 ◽  
Author(s):  
Anne Robert ◽  
Françoise Benoit-Vical ◽  
Odile Dechy-Cabaret ◽  
Bernard Meunier
Keyword(s):  
Mechanism Of Action ◽  
Antimalarial Activity ◽  
Short Review ◽  
Mechanisms Of Action ◽  
Antimalarial Drugs ◽  
Molecular Aspect ◽  
New Compounds

A short review of the antimalarial drugs currently used in human clinics is reported. The molecular aspect of the different possible mechanisms of action of artemisinin is documented, including recent data on heme alkylation. The preparation and the in vitro antimalarial activity of new modular molecules named "trioxaquines" are also presented.

scholarly journals Inhibition of Heme Polymerization Invitro Assay Of Extract of Sirih Leaf (Piper betle Linn.) and Sun Flower Leaves (Helianthus annuus L.)

2020 ◽  
Vol 7 (1) ◽  
pp. 22 ◽  
Author(s):  
Ami Tjitraresmi ◽  
Moelyono Moektiwardoyo ◽  
Yasmiwar Susilawati
Keyword(s):  
Helianthus Annuus ◽  
Antimalarial Activity ◽  
Antimalarial Drugs ◽  
Piper Betle ◽  
Phytochemical Screening ◽  
Helianthus Annuus L ◽  
Betel Leaf ◽  
The People ◽  
Ic50 Values

Malaria is a disease that occurs in tropical countries like Indonesia. The incidence of malaria in the world is still quite high and the occurrence of cases of Plasmodium resistance to antimalarial drugs and the widespread of resistance have prompted researchers to look for new antimalarial drugs, especially from natural materials. Betel leaf (Piper betle Linn.) And sunflower leaf (Helianthus annuus L.) have long been used by the people of Indonesia as an antimalarial drug. The purpose of this study was to determine antimalarial activity through inhibition of heme polymerization and determine secondary metabolite compounds by phytochemical screening from betel leaves and sunflower leaves. The heme polymerization inhibition activity assay was carried out by the in-vitro method using a microplate reader at 415 nm and 630 nm wavelengths. IC50 values of betel leaf extract and sunflower leaf were 178.67 μg/ml and 160.10 μg/ml, respectively. Phytochemical screening results from betel leaf showed the presence of flavonoids, polyphenols, tannins, quinones, saponins, and monoterpenoids-sesquiterpenoids, while sunflower leaves contain alkaloids, polyphenols, flavonoids, steroids and monoterpenoids-sesquiterpenoids.Keywords: Piper betle Linn., Helianthus annuus L., Malaria, Heme Polymerization

scholarly journals In Vitro Assessment of Antiplasmodial Activity and Cytotoxicity of Polyalthia longifolia Leaf Extracts on Plasmodium falciparum Strain NF54

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Bethel Kwansa-Bentum ◽  
Kojo Agyeman ◽  
Jeffrey Larbi-Akor ◽  
Claudia Anyigba ◽  
Regina Appiah-Opong
Keyword(s):  
Plasmodium Falciparum ◽  
Ethyl Acetate ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Radical Scavenging ◽  
Antimalarial Drugs ◽  
Antiplasmodial Activity ◽  
Leaf Extracts ◽  
Polyalthia Longifolia

Background. Malaria is one of the most important life-threatening infectious diseases in the tropics. In spite of the effectiveness of artemisinin-based combination therapy, reports on reduced sensitivity of the parasite to artemisinin in Cambodia and Thailand warrants screening for new potential antimalarial drugs for future use. Ghanaian herbalists claim that Polyalthia longifolia has antimalarial activity. Therefore, antiplasmodial activity, cytotoxic effects, and antioxidant and phytochemical properties of P. longifolia leaf extract were investigated in this study. Methodology/Principal Findings. Aqueous, 70% hydroethanolic and ethyl acetate leaf extracts were prepared using standard procedures. Antiplasmodial activity was assessed in vitro by using chloroquine-sensitive malaria parasite strain NF54. The SYBR® Green and tetrazolium-based calorimetric assays were used to measure parasite growth inhibition and cytotoxicity, respectively, after extract treatment. Total antioxidant activity was evaluated using a free radical scavenging assay. Results obtained showed that extracts protected red blood cells against Plasmodium falciparum mediated damage. Fifty percent inhibitory concentration (IC50) values were 24.0±1.08 μg/ml, 22.5±0.12 μg/ml, and 9.5±0.69 μg/ml for aqueous, hydroethanolic, and ethyl acetate extracts, respectively. Flavonoids, tannins, and saponins were present in the hydroethanolic extract, whereas only the latter was observed in the aqueous extract. Aqueous and hydroethanolic extracts showed stronger antioxidant activities compared to the ethyl acetate extract. Conclusions/Significance. The extracts of P. longifolia have antiplasmodial properties and low toxicities to human red blood cells. The extracts could be developed as useful alternatives to antimalarial drugs. These results support claims of the herbalists that decoctions of P. longifolia are useful antimalarial agents.

The in vitro antimalarial interaction of 9-hydroxycalabaxanthone and α-mangostin with mefloquine/artesunate

2014 ◽  
Vol 60 (1) ◽  
Author(s):  
Wanna Chaijaroenkul ◽  
Kesara Na-Bangchang
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Drug Concentration ◽  
Combination Index ◽  
Antimalarial Drugs ◽  
Antagonistic Effect ◽  
Parasite Growth ◽  
Major Health Problem ◽  
Major Health

AbstractMultidrug resistance Plasmodium falciparum is the major health problem in Thailand. Discovery and development of new antimalarial drugs with novel modes of action is urgently required. The aim of the present study was to investigate the antimalarial interaction of 9-hydroxycalabaxanthone and α-mangostin with the standard antimalarial drugs mefloquine and artesunate in chloroquine sensitive (3D7) and chloroquine resistant (K1) P. falciparum clones in vitro. Median (range) IC50 (drug concentration which produces 50% parasite growth inhibition) values of the 9-hydroxycalabaxanthone, α-mangostin, artesunate and mefloquine for 3D7 vs K1 clones were 1.5 (0.9-2.1) vs 1.2 (1.1-1.6) μM, 17.9 (15.7.0-20.0) vs 9.7 (6.0-14.0) μM, 1.0 (0.4-3.0) vs 1.7 (1.0-2.5) nM, and 13.3 (11.1-13.3) vs 7.1 (6.7-12.2) nM, respectively. Analysis of isobologram and combination index (CI) of 9-hydroxycalabaxanthone with artesunate or mefloquine showed synergistic and indifference antimalarial interaction, respectively. α-mangostin-artesunate combination exhibited a slight antagonistic effect of antimalarial interaction, whereas α-mangostin and mefloquine combination showed indifference interaction in both clones. The combination of 9-hydroxycalabaxanthone with α-mangostin showed the synergistic antimalarial interaction in both clones

scholarly journals Plasmodium falciparum Resistance to a Lead Benzoxaborole Due to Blocked Compound Activation and Altered Ubiquitination or Sumoylation

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Kirthana M. V. Sindhe ◽  
Wesley Wu ◽  
Jenny Legac ◽  
Yong-Kang Zhang ◽  
Eric E. Easom ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Stress Responses ◽  
Mechanisms Of Action ◽  
Antimalarial Drugs ◽  
New Drugs ◽  
Loss Of Function ◽  
Content Type ◽  
High Level ◽  
Level Resistance

ABSTRACT New antimalarial drugs are needed. The benzoxaborole AN13762 showed excellent activity against cultured Plasmodium falciparum, against fresh Ugandan P. falciparum isolates, and in murine malaria models. To gain mechanistic insights, we selected in vitro for P. falciparum isolates resistant to AN13762. In all of 11 independent selections with 100 to 200 nM AN13762, the 50% inhibitory concentration (IC50) increased from 18–118 nM to 180–890 nM, and whole-genome sequencing of resistant parasites demonstrated mutations in prodrug activation and resistance esterase (PfPARE). The introduction of PfPARE mutations led to a similar level of resistance, and recombinant PfPARE hydrolyzed AN13762 to the benzoxaborole AN10248, which has activity similar to that of AN13762 but for which selection of resistance was not readily achieved. Parasites further selected with micromolar concentrations of AN13762 developed higher-level resistance (IC50, 1.9 to 5.0 μM), and sequencing revealed additional mutations in any of 5 genes, 4 of which were associated with ubiquitination/sumoylation enzyme cascades; the introduction of one of these mutations, in SUMO-activating enzyme subunit 2, led to a similar level of resistance. The other gene mutated in highly resistant parasites encodes the P. falciparum cleavage and specificity factor homolog PfCPSF3, previously identified as the antimalarial target of another benzoxaborole. Parasites selected for resistance to AN13762 were cross-resistant with a close analog, AN13956, but not with standard antimalarials, AN10248, or other benzoxaboroles known to have different P. falciparum targets. Thus, AN13762 appears to have a novel mechanism of antimalarial action and multiple mechanisms of resistance, including loss of function of PfPARE preventing activation to AN10248, followed by alterations in ubiquitination/sumoylation pathways or PfCPSF3. IMPORTANCE Benzoxaboroles are under study as potential new drugs to treat malaria. One benzoxaborole, AN13762, has potent activity and promising features, but its mechanisms of action and resistance are unknown. To gain insights into these mechanisms, we cultured malaria parasites with nonlethal concentrations of AN13762 and generated parasites with varied levels of resistance. Parasites with low-level resistance had mutations in PfPARE, which processes AN13762 into an active metabolite; PfPARE mutations prevented this processing. Parasites with high-level resistance had mutations in any of a number of enzymes, mostly those involved in stress responses. Parasites selected for AN13762 resistance were not resistant to other antimalarials, suggesting novel mechanisms of action and resistance for AN13762, a valuable feature for a new class of antimalarial drugs.

scholarly journals Polyamidoamine Nanoparticles for the Oral Administration of Antimalarial Drugs

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 225 ◽  
Author(s):  
Elisabet Martí Coma-Cros ◽  
Arnau Biosca ◽  
Joana Marques ◽  
Laura Carol ◽  
Patricia Urbán ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Plasmodium Yoelii ◽  
Antimalarial Drugs ◽  
Mass Spectrometry Analysis ◽  
Parasite Invasion ◽  
Spectrometry Analysis ◽  
Anopheles Atroparvus ◽  
Oral Formulations ◽  
Preferential Binding ◽  
Direct Administration

Current strategies for the mass administration of antimalarial drugs demand oral formulations to target the asexual Plasmodium stages in the peripheral bloodstream, whereas recommendations for future interventions stress the importance of also targeting the transmission stages of the parasite as it passes between humans and mosquitoes. Orally administered polyamidoamine (PAA) nanoparticles conjugated to chloroquine reached the blood circulation and cured Plasmodium yoelii-infected mice, slightly improving the activity of the free drug and inducing in the animals immunity against malaria. Liquid chromatography with tandem mass spectrometry analysis of affinity chromatography-purified PAA ligands suggested a high adhesiveness of PAAs to Plasmodium falciparum proteins, which might be the mechanism responsible for the preferential binding of PAAs to Plasmodium-infected erythrocytes vs. non-infected red blood cells. The weak antimalarial activity of some PAAs was found to operate through inhibition of parasite invasion, whereas the observed polymer intake by macrophages indicated a potential of PAAs for the treatment of certain coinfections such as Plasmodium and Leishmania. When fluorescein-labeled PAAs were fed to females of the malaria mosquito vectors Anopheles atroparvus and Anopheles gambiae, persistent fluorescence was observed in the midgut and in other insect’s tissues. These results present PAAs as a versatile platform for the encapsulation of orally administered antimalarial drugs and for direct administration of antimalarials to mosquitoes, targeting mosquito stages of Plasmodium.

scholarly journals Evaluation of Antimalarial Activity of Methanolic Root Extract of Myrica salicifolia A Rich (Myricaceae) Against Plasmodium berghei–Infected Mice

2020 ◽  
Vol 25 ◽  
pp. 2515690X2092053 ◽  
Author(s):  
Zemene Demelash Kifle ◽  
Getnet Mequanint Adinew ◽  
Mestayet Geta Mengistie ◽  
Abyot Endale Gurmu ◽  
Engidaw Fentahun Enyew ◽  
...  
Keyword(s):  
Crude Extract ◽  
Plasmodium Berghei ◽  
Antimalarial Activity ◽  
Effective Vaccine ◽  
Root Extract ◽  
Honestly Significant Difference ◽  
Significant Difference ◽  
And Control

Background. The management and control of malaria has become gradually challenging due to the spread of drug-resistant parasites, lack of effective vaccine, and the resistance of vector to insecticides. Consequently, novel agents are urgently needed from different sources including from medicinal plants. In Ethiopia and Uganda, Myrica salicifolia root is traditionally claimed for the treatment of malaria. The aim of this study was to evaluate the in vivo antimalarial activity of root crude extract of M salicifolia. Methods. The parasite, Plasmodium berghei was used in this study since it is an appropriate parasite that is most commonly used because of its higher accessibility. A 4-day suppressive test was employed to evaluate the antimalarial effect of crude extract against early infection. The curative and prophylactic effect of the crude extract was further tested by Rane’s test and residual infection procedure. Parasitemia, survival time, packed cell volume, body weight, and rectal temperature of mice were used as evaluation parameters. Windows SPSS version 24 was used to analyze the data and analysis of variance followed by Tukey’s honestly significant difference to compare results between groups. Results. The root crude extract of M salicifolia significantly ( P < .05-.0001) suppressed parasitemia. The crude extract exhibited a chemosuppression of 40.90. Conclusion. The development of new antimalarial agents and the finding supports the traditional claims and previous in vitro studies.

Docking Studies of Structurally Diverse Antimalarial Drugs Targeting PfATP6: No Correlation between in silico Binding Affinity and in vitro Antimalarial Activity.

ChemMedChem ◽  
2009 ◽  
Vol 4 (9) ◽  
pp. 1469-1479 ◽  
Author(s):  
Fatima Bousejra-El Garah ◽  
Jean-Luc Stigliani ◽  
Frédéric Coslédan ◽  
Bernard Meunier ◽  
Anne Robert
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Antimalarial Activity ◽  
Docking Studies ◽  
Antimalarial Drugs

scholarly journals Artemisinin – Based Drugs Target the Plasmodium falciparum heme-detoxification pathway

2021 ◽  
Author(s):  
Kaleab A. Ribbiso ◽  
Laura E. Heller ◽  
Abigail Taye ◽  
Erin Julian ◽  
Andreas V. Willems ◽  
...  
Keyword(s):  
Antimalarial Drugs ◽  
Parasite Growth ◽  
Inhibition Assay ◽  
Combination Therapies ◽  
Digestive Vacuole ◽  
Reducing Conditions ◽  
Free Heme ◽  
Order Of Magnitude ◽  
Detoxification Pathway

Artemisinin – based antimalarial drugs are believed to exert lethal effects on malarial parasites by alkylating a variety of intracellular molecular targets. Recent work with live parasites has shown that one of the alkylated targets is free heme within the parasite digestive vacuole, which is liberated upon hemoglobin catabolism by the intraerythrocytic parasite, and that reduced levels of heme alkylation occur in artemisinin resistant parasites. One implication of heme alkylation is that these drugs may inhibit parasite detoxification of free heme via inhibition of heme to hemozoin crystallization; however, previous reports that have investigated this hypothesis present conflicting data. By controlling reducing conditions and hence the availability of ferrous vs ferric forms of free heme, we modify a previously reported hemozoin inhibition assay to quantify the ability of ART – based drugs to target the heme detoxification pathway under reduced vs oxidizing conditions. Contrary to some previous reports, we find that artemisinins are potent inhibitors of hemozoin crystallization, with effective half maximal concentrations approximately an order of magnitude lower than those for most quinoline – based antimalarial drugs. We also examine hemozoin and in vitro parasite growth inhibition for drug pairs found in the most commonly used ART – based combination therapies (ACTs). All ACTs examined inhibit hemozoin crystallization in an additive fashion, and all but one inhibit parasite growth in additive fashion.

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