scholarly journals Hybrid Gold(I) NHC-Artemether Complexes to Target Falciparum Malaria Parasites

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2817
Author(s):  
Manel Ouji ◽  
Guillaume Barnoin ◽  
Álvaro Fernández Álvarez ◽  
Jean-Michel Augereau ◽  
Catherine Hemmert ◽  
...  
Keyword(s):  
Public Health ◽  
Plasmodium Falciparum ◽  
Mammalian Cells ◽  
Antimalarial Drugs ◽  
Cross Resistance ◽  
Major Threat ◽  
Hybrid Molecules ◽  
Low Cytotoxicity ◽  
Nanomolar Range

The emergence of Plasmodium falciparum parasites, responsible for malaria disease, resistant to antiplasmodial drugs including the artemisinins, represents a major threat to public health. Therefore, the development of new antimalarial drugs or combinations is urgently required. In this context, several hybrid molecules combining a dihydroartemisinin derivative and gold(I) N-heterocyclic carbene (NHC) complexes have been synthesized based on the different modes of action of the two compounds. The antiplasmodial activity of these molecules was assessed in vitro as well as their cytotoxicity against mammalian cells. All the hybrid molecules tested showed efficacy against P. falciparum, in a nanomolar range for the most active, associated with a low cytotoxicity. However, cross-resistance between artemisinin and these hybrid molecules was evidenced. These results underline a fear about the risk of cross-resistance between artemisinins and new antimalarial drugs based on an endoperoxide part. This study thus raises concerns about the use of such molecules in future therapeutic malaria policies.

scholarly journals Frequency of drug resistance in Plasmodium falciparum: a nonsynergistic combination of 5-fluoroorotate and atovaquone suppresses in vitro resistance.

1996 ◽  
Vol 40 (4) ◽  
pp. 914-919 ◽  
Author(s):  
S Gassis ◽  
P K Rathod
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Mammalian Cells ◽  
Cross Resistance ◽  
Synergistic Activity ◽  
Individual Resistance ◽  
In Vitro Method ◽  
Proof Of Principle

A combination of 5-fluoroorotate and atovaquone eliminated Plasmodium falciparum in long-term cultures more efficiently than either compound alone. The improved potency came not through synergistic activity but through decreased frequency of drug resistance. In support of this finding, it was shown that 5-fluoroorotate and atovaquone do not act in a synergistic fashion, that 5-fluoroorotate-resistant and atovaquone-resistant P. falciparum organisms generated in vitro do not show cross-resistance, and that the frequency of simultaneous resistance to the two compounds approached the product of their individual resistance frequencies. To demonstrate the last finding, and establish proof of principle, an in vitro method was developed for measuring the frequency of drug resistance in P. falciparum. By this method, it was shown that the frequency of resistance to 10(-7) M 5-fluoroorotate was about 10(-6) and the frequency of resistance to 10(-8) M atovaquone was about 10(-5); the frequency of simultaneous resistance to a combination of 10(-7) M 5-fluoroorotate and 10(-8) M atovaquone was less than 5 x 10(-10). On the basis of additional measurements, it was estimated that the frequency of simultaneous resistance to higher, pharmacologically more relevant, concentrations of 10(-6) M 5-fluoroorotate and 10(-7) M atovaquone would be less than 10(-17). Control experiments demonstrated that these drug combinations did not cause increased toxicity to mammalian cells in culture. On this basis, it is predicted that a combination of 5-fluoroorotate and atovaquone will successfully eliminate typical malarial infections in animals and in human patients at doses that are readily tolerated.

scholarly journals In Vitro Activities of Benflumetol against 158 Senegalese Isolates of Plasmodium falciparum in Comparison with Those of Standard Antimalarial Drugs

1999 ◽  
Vol 43 (2) ◽  
pp. 418-420 ◽  
Author(s):  
Bruno Pradines ◽  
Adama Tall ◽  
Thierry Fusai ◽  
Andre Spiegel ◽  
Remi Hienne ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Concentration ◽  
Antimalarial Drugs ◽  
Cross Resistance ◽  
Alternative Drug

ABSTRACT The 50% inhibitory concentration (IC50s) of benflumetol (range, 12.5 to 240 nM; mean, 55.1 nM) for 158 Senegalese isolates were evaluated. Ten isolates (6%) showed decreased susceptibility to benflumetol. Benflumetol was slightly more potent against chloroquine-resistant isolates (P < 0.025). No correlation or weak correlations in the responses to benflumetol and pyrimethamine, chloroquine, amodiaquine, artemether, quinine, and pyronaridine were observed, and these correlations are insufficient to suggest cross-resistance. Benflumetol may be an important alternative drug for the treatment of chloroquine-resistant malaria.

scholarly journals Atorvastatin Is a Promising Partner for Antimalarial Drugs in Treatment of Plasmodium falciparum Malaria

2009 ◽  
Vol 53 (6) ◽  
pp. 2248-2252 ◽  
Author(s):  
Véronique Parquet ◽  
Sébastien Briolant ◽  
Marylin Torrentino-Madamet ◽  
Maud Henry ◽  
Lionel Almeras ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Reductase Inhibitor ◽  
Significant Positive Correlation ◽  
Plasmodium Falciparum Malaria ◽  
Antimalarial Drugs ◽  
Transport Proteins ◽  
Cross Resistance ◽  
Antimalarial Drug Resistance

ABSTRACT Atorvastatin (AVA) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. AVA exposure resulted in the reduced in vitro growth of 22 Plasmodium falciparum strains, with the 50% inhibitory concentrations (IC50s) ranging from 2.5 μM to 10.8 μM. A significant positive correlation was found between the strains’ responses to AVA and mefloquine (r = 0.553; P = 0.008). We found no correlation between the responses to AVA and to chloroquine, quinine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone, or doxycycline. These data could suggest that the mechanism of AVA uptake and/or the mode of action of AVA is different from those for other antimalarial drugs. The IC50s for AVA were unrelated to the occurrence of mutations in the transport protein genes involved in quinoline antimalarial drug resistance, such as the P. falciparum crt, mdr1, mrp, and nhe-1 genes. Therefore, AVA can be ruled out as a substrate for the transport proteins (CRT, Pgh1, and MRP) and is not subject to the pH modification induced by the P. falciparum NHE-1 protein. The absence of in vitro cross-resistance between AVA and chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone, and doxycycline argues that these antimalarial drugs could potentially be paired with AVA as a treatment for malaria. In conclusion, the present observations suggest that AVA is a good candidate for further studies on the use of statins in association with drugs known to have activities against the malaria parasite.

scholarly journals Absence of Association between Methylene Blue Reduced Susceptibility and Polymorphisms in 12 Genes Involved in Antimalarial Drug Resistance in African Plasmodium falciparum

2021 ◽  
Vol 14 (4) ◽  
pp. 351
Author(s):  
Mathieu Gendrot ◽  
Océane Delandre ◽  
Marie Robert ◽  
Francis Foguim ◽  
Nicolas Benoit ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Antimalarial Drug ◽  
Antimalarial Drugs ◽  
New Drugs ◽  
Cross Resistance ◽  
Antimalarial Drug Resistance ◽  
In Vitro Susceptibility

Half the human population is exposed to malaria. Plasmodium falciparum antimalarial drug resistance monitoring and development of new drugs are major issues related to the control of malaria. Methylene blue (MB), the oldest synthetic antimalarial, is again a promising drug after the break of its use as an antimalarial drug for more than 80 years and a potential partner for triple combination. Very few data are available on the involvement of polymorphisms on genes known to be associated with standard antimalarial drugs and parasite in vitro susceptibility to MB (cross-resistance). In this context, MB susceptibility was evaluated against 482 isolates of imported malaria from Africa by HRP2-based ELISA chemosusceptibility assay. A total of 12 genes involved in antimalarial drug resistance (Pfcrt, Pfdhfr, Pfmdr1, Pfmdr5, Pfmdr6, PfK13, Pfubq, Pfcarl, Pfugt, Pfact, Pfcoronin, and copy number of Pfpm2) were sequenced by Sanger method and quantitative PCR. On the Pfmdr1 gene, the mutation 86Y combined with 184F led to more susceptible isolates to MB (8.0 nM vs. 11.6 nM, p = 0.03). Concerning Pfmdr6, the isolates bearing 12 Asn repetitions were more susceptible to MB (4.6 nM vs. 11.6 nM, p = 0.005). None of the polymorphisms previously described as involved in antimalarial drug resistance was shown to be associated with reduced susceptibility to MB. Some genes (particularly PfK13, Pfugt, Pfact, Pfpm2) did not present enough genetic variability to draw conclusions about their involvement in reduced susceptibility to MB. None of the polymorphisms analyzed by multiple correspondence analysis (MCA) had an impact on the MB susceptibility of the samples successfully included in the analysis. It seems that there is no in vitro cross-resistance between MB and commonly used antimalarial drugs.

Drug sensitivity of Plasmodium falciparum field isolates to selected antimalarial drugs in Ghana using the in-vitro DAPI assay

2020 ◽  
Author(s):  
Michael Fokuo Ofori ◽  
Emma E. Kploanyi ◽  
Benedicta A. Mensah ◽  
Emmanuel K. Dickson ◽  
Eric Kyei Baafour ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Sensitivity ◽  
Geometric Mean ◽  
Antimalarial Drugs ◽  
Chloroquine Resistance ◽  
Cape Coast ◽  
African Region ◽  
Cross Sectional ◽  
Ecological Zones

Abstract Background: Malaria continues to be a major health issue globally with nine out of ten cases reported in Africa. Although the current artemisinin derived combination therapies in Ghana are still efficacious against the Plasmodium falciparum parasite, compounding evidence of artemisinin and amodiaquine resistance in the African region establish the need for a full, up-to-date understanding and monitoring of antimalarial resistance to provide evidence for planning control strategies.Methods: The study was cross-sectional and was conducted during the peak transmission seasons of 2015, 2016, and 2017 in two study sites located in different ecological zones of Ghana involving children aged 0.5-14 years presenting with symptomatic uncomplicated Plasmodium falciparum (Pf) malaria with parasitaemia greater than 1000 parasites/µl of blood. Using in vitro 4-,6-diamidino-2-phenylindole (DAPI) drug sensitivity assays, 328 Pf parasites collected were used to investigate susceptibility to five selected antimalarial drugs: chloroquine, amodiaquine, dihydroartemisinin, artesunate and mefloquine.Results: The geometric mean B (GMIC50) of five drugs against the parasites collected from Cape Coast were 9.6, 23.6, 9.1, 3.5 and 8.1nM for chloroquine, amodiaquine, artemisinin, artesunate, and mefloquine respectively in 2015. There was a 2 fold increase in the GMIC50 levels of all the drugs against the isolates collected in 2016 as compared to the 2015 data from Cape Coast .The a of the five drugs against the parasites collected from Cape Coast were significantly higher than those isolates collected from Begoro in 2016 and 2017 (P<0.001) . The chloroquine resistance ranged between 1.9% and 9.1% among isolates collected from Cape Coast but remained 0% in Begoro over the period. High amodiaquine resistance levels were recorded at both sites whilst that of artesunate resistance ranged between 4 and 10% over the study period.Conclusions: The study has assessed the antimalarial drug sensitivities of Ghanaian Pf isolates collected over 3 consecutive years. The parasites showed variable resistance levels to all the drugs used over the period. The study has demonstrated the continual return of chloroquine-sensitive parasites. The in vitro DAPI assay is a useful method for monitoring individual drugs used in combinations in Ghana for the generation of data on their sensitivities over time.

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 Liposomes Composed by Membrane Lipid Extracts from Macrophage Cell Line as a Delivery of the Trypanocidal N,N’-Squaramide 17 towards Trypanosoma cruzi

Materials ◽  
2020 ◽  
Vol 13 (23) ◽  
pp. 5505
Author(s):  
Christian Rafael Quijia ◽  
Cínthia Caetano Bonatto ◽  
Luciano Paulino Silva ◽  
Milene Aparecida Andrade ◽  
Clenia Santos Azevedo ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Mammalian Cells ◽  
Entrapment Efficiency ◽  
Membrane Lipid ◽  
Raw 264.7 Cells ◽  
Hydrodynamic Diameter ◽  
Raw 264.7 ◽  
Low Cytotoxicity

Chagas is a neglected tropical disease caused by Trypanosoma cruzi, and affects about 25 million people worldwide. N, N’-Squaramide 17 (S) is a trypanocidal compound with relevant in vivo effectiveness. Here, we produced, characterized, and evaluated cytotoxic and trypanocidal effects of macrophage-mimetic liposomes from lipids extracted of RAW 264.7 cells to release S. As results, the average hydrodynamic diameter and Zeta potential of mimetic lipid membranes containing S (MLS) was 196.5 ± 11 nm and −61.43 ± 2.3 mV, respectively. Drug entrapment efficiency was 73.35% ± 2.05%. After a 72 h treatment, MLS was observed to be active against epimastigotes in vitro (IC50 = 15.85 ± 4.82 μM) and intracellular amastigotes (IC50 = 24.92 ± 4.80 μM). Also, it induced low cytotoxicity with CC50 of 1199.50 ± 1.22 μM towards VERO cells and of 1973.97 ± 5.98 μM in RAW 264.7. MLS also induced fissures in parasite membrane with a diameter of approximately 200 nm in epimastigotes. MLS showed low cytotoxicity in mammalian cells and high trypanocidal activity revealing this nanostructure a promising candidate for the development of Chagas disease treatment.

scholarly journals Reversal of Mefloquine and Quinine Resistance in Plasmodium falciparum with NP30

2003 ◽  
Vol 47 (8) ◽  
pp. 2393-2396 ◽  
Author(s):  
Michelle Ciach ◽  
Kathleen Zong ◽  
Kevin C. Kain ◽  
Ian Crandall
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Genetic Analysis ◽  
Resistance Genes ◽  
Mammalian Cells ◽  
Point Mutations ◽  
In Vitro Assays ◽  
Drug Efflux ◽  
P Glycoprotein

ABSTRACT Quinoline resistance in malaria is frequently compared with P-glycoprotein-mediated multidrug resistance (mdr) in mammalian cells. We have previously reported that nonylphenolethoxylates, such as NP30, are potential Plasmodium falciparum P-glycoprotein substrates and drug efflux inhibitors. We used in vitro assays to compare the ability of verapamil and NP30 to sensitize two parasite isolates to four quinolines: chloroquine (CQ), mefloquine (MF), quinine (QN), and quinidine (QD). NP30 was able to sensitize (reversal, >80%) P. falciparum to MF, QN, QD, and, to a lesser extent, CQ. The presence of 2 μM verapamil had no effect on mefloquine resistance; however, the presence of verapamil modulated the activities of QN and QD in a manner parallel to that observed for CQ. Genetic analysis of putative quinoline resistance genes did not suggest an association between known point mutations in pfcrt and pfmdr1 and NP30 sensitization activity. We conclude that the sensitization action of NP30 is distinct both phenotypically and genotypically from that of verapamil.

Sign in / Sign up

Export Citation Format

Share Document