Plants as Sources of Antimalarial Drugs, Part 4: Activity of Brucea javanica Fruits Against Chloroquine-Resistant Plasmodium falciparum in vitro and Against Plasmodium berghei in vivo

Background and Objectives. Artemisinin is the popular antimalarial medication, but it has to be used in combination with other drugs as its monotherapy causes resistance. The effectiveness of eosin B, a laboratory stain, as a competent antimalarial agent was identified earlier. It was tested in combination with different antimalarial drugs such as artesunate (a derivative of artemisinin) or chloroquine or sulphadoxine-pyrimethamine in vitro on Plasmodium falciparum and in vivo on Plasmodium berghei using Peter’s suppression test. Methods. Drug assessment was carried out singly or in combination on Plasmodium falciparum in vitro using the candle jar method at three inhibitory concentrations. Percent parasitemia of live cells was obtained by microscopic counting. Peter’s suppression test was carried out on mice infected with Plasmodium berghei after 3 administration of the drugs singly and in combination, and parasites were counted by microscopy for 10 days. Results. Synergy was exhibited by isobolograms of eosin B combined with artesunate and sulphadoxine-pyrimethamine with more than 10 fold reduction of all drugs in vitro. A good combination index was obtained with artesunate at 50% inibitory concentration with 3.4 nM eosin B and 1.7 nM artesunate in contrast to 124 nM eosin B and 7.6 nM artesunate singly. In vivo studies also showed a considerable lowering of the effective dose of eosin B 30 mg/kg: artesunate 3 mg/kg with 200 mg/kg eosin B and 60 mg/kg artesunate separately. Sulphadoxine-pyrimethamine seemed to have the greatest synergistic effect with a combination index of 0.007, but this could be due to it consisting of a combination of three drugs. Eosin B’s combination index with chloroquine was fair, and in vivo tests too did not show as much competence as the other two drugs. Conclusion and Interpretation. It can be concluded that eosin B can be used in combination with antimalarial drugs with favorable results.

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Antimalarial Activity of Phenazines from Lapachol, β-Lapachone and Its Derivatives Against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.

ChemInform ◽

10.1002/chin.200426191 ◽

2004 ◽

Vol 35 (26) ◽

Author(s):

Valter F. de Andrade-Neto ◽

Marilia O. F. Goulart ◽

Jorge F. da Silva Filho ◽

Matuzalem J. da Silva ◽

Maria do Carmo F. R. Pinto ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Plasmodium Berghei ◽

Antimalarial Activity

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The Development of Novel Compounds Against Malaria: Quinolines, Triazolpyridines, Pyrazolopyridines and Pyrazolopyrimidines

Molecules ◽

10.3390/molecules24224095 ◽

2019 ◽

Vol 24 (22) ◽

pp. 4095 ◽

Cited By ~ 11

Author(s):

Luiz C. S. Pinheiro ◽

Lívia M. Feitosa ◽

Marilia O. Gandi ◽

Flávia F. Silveira ◽

Nubia Boechat

Keyword(s):

Plasmodium Falciparum ◽

Mouse Model ◽

Infected Mouse ◽

Plasmodium Berghei ◽

Medicinal Chemistry ◽

Quinoline Derivatives ◽

Dihydroorotate Dehydrogenase ◽

New Compounds

Based on medicinal chemistry tools, new compounds for malaria treatment were designed. The scaffolds of the drugs used to treat malaria, such as chloroquine, primaquine, amodiaquine, mefloquine and sulfadoxine, were used as inspiration. We demonstrated the importance of quinoline and non-quinoline derivatives in vitro with activity against the W2 chloroquine-resistant (CQR) Plasmodium falciparum clone strain and in vivo against Plasmodium berghei-infected mouse model. Among the quinoline derivatives, new hybrids between chloroquine and sulfadoxine were designed, which gave rise to an important prototype that was more active than both chloroquine and sulfadoxine. Hybrids between chloroquine–atorvastatin and primaquine–atorvastatin were also synthesized and shown to be more potent than the parent drugs alone. Additionally, among the quinoline derivatives, new mefloquine derivatives were synthesized. Among the non-quinoline derivatives, we obtained excellent results with the triazolopyrimidine nucleus, which gave us prototype I that inspired the synthesis of new heterocycles. The pyrazolopyrimidine derivatives stood out as non-quinoline derivatives that are potent inhibitors of the P. falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme. We also examined the pyrazolopyridine and pyrazolopyrimidine nuclei.

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Resistance of Plasmodium falciparum to antimalarial drugs in a highly endemic area of southern Viet Nam: a study in vivo and in vitro

Transactions of the Royal Society of Tropical Medicine and Hygiene ◽

10.1016/s0035-9203(01)90254-8 ◽

2001 ◽

Vol 95 (3) ◽

pp. 325-329 ◽

Cited By ~ 30

Author(s):

Nguyen Mai Huong ◽

Sean Hewitt ◽

Timothy M.E. Davis ◽

Le Duc Dao ◽

Tran Quoc Toan ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Endemic Area ◽

Antimalarial Drugs ◽

Viet Nam

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Andrographolide: A Novel Antimalarial Diterpene Lactone Compound fromAndrographis paniculataand Its Interaction with Curcumin and Artesunate

Journal of Tropical Medicine ◽

10.1155/2011/579518 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 27

Author(s):

Kirti Mishra ◽

Aditya P. Dash ◽

Nrisingha Dey

Keyword(s):

Plasmodium Falciparum ◽

Life Span ◽

Plasmodium Berghei ◽

Antimalarial Activity ◽

Andrographis Paniculata ◽

Antiplasmodial Activity ◽

Template Molecule

Andrographolide (AND), the diterpene lactone compound, was purified by HPLC from the methanolic fraction of the plantAndrographis paniculata. The compound was found to have potent antiplasmodial activity when tested in isolation and in combination with curcumin and artesunate against the erythrocytic stages ofPlasmodium falciparum in vitroandPlasmodium bergheiANKAin vivo. IC50s for artesunate (AS), andrographolide (AND), and curcumin (CUR) were found to be 0.05, 9.1 and 17.4 μM, respectively. The compound (AND) was found synergistic with curcumin (CUR) and addictively interactive with artesunate (AS).In vivo, andrographolide-curcumin exhibited better antimalarial activity, not only by reducing parasitemia (29%), compared to the control (81%), but also by extending the life span by 2-3 folds. Being nontoxic to thein vivosystem this agent can be used as template molecule for designing new derivatives with improved antimalarial properties.

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New quinoline derivatives demonstrate a promising antimalarial activity against Plasmodium falciparum in vitro and Plasmodium berghei in vivo

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2015.04.014 ◽

2015 ◽

Vol 25 (11) ◽

pp. 2308-2313 ◽

Cited By ~ 24

Author(s):

Roberta Reis Soares ◽

José Marcio Fernandes da Silva ◽

Bianca Cecheto Carlos ◽

Camila Campos da Fonseca ◽

Laila Salomé Araújo de Souza ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Plasmodium Berghei ◽

Antimalarial Activity ◽

Quinoline Derivatives

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Complex Polymorphisms in the Plasmodium falciparum Multidrug Resistance Protein 2 Gene and Its Contribution to Antimalarial Response

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03337-14 ◽

2014 ◽

Vol 58 (12) ◽

pp. 7390-7397 ◽

Cited By ~ 17

Author(s):

Maria Isabel Veiga ◽

Nuno S. Osório ◽

Pedro Eduardo Ferreira ◽

Oscar Franzén ◽

Sabina Dahlstrom ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Multidrug Resistance ◽

Abc Transporter ◽

Parasite Clearance ◽

Antimalarial Drugs ◽

Multidrug Resistance Protein ◽

Content Type ◽

Resistance Protein

ABSTRACTPlasmodium falciparumhas the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including theApicomplexaparasites.P. falciparumgenome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters:Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studiedPfmrp2. The role ofPfmrp2polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of thePfmrp2genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found thatPfmrp2harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identifiedPfmrp2polymorphisms with alteredin vitrosusceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggestedPfmrp2polymorphisms modulate the parasite'sin vitroresponse to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association within vivoparasite clearance. In conclusion, our study reveals that thePfmrp2gene is the most diverse ABC transporter known inP. falciparumwith a potential role in antimalarial drug resistance.

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Chemical Attenuation of Plasmodium berghei Sporozoites Induces Sterile Immunity in Mice

Infection and Immunity ◽

10.1128/iai.01399-07 ◽

2008 ◽

Vol 76 (3) ◽

pp. 1193-1199 ◽

Cited By ~ 42

Author(s):

Lisa A. Purcell ◽

Stephanie K. Yanow ◽

Moses Lee ◽

Terry W. Spithill ◽

Ana Rodriguez

Keyword(s):

Plasmodium Falciparum ◽

Plasmodium Berghei ◽

Alkylating Agent ◽

Blood Stage ◽

Wild Type ◽

Vaccine Strategy ◽

Liver Stage ◽

Stage Development

ABSTRACT Radiation and genetic attenuation of Plasmodium sporozoites are two approaches for whole-organism vaccines that protect against malaria. We evaluated chemical attenuation of sporozoites as an alternative vaccine strategy. Sporozoites were treated with the DNA sequence-specific alkylating agent centanamycin, a compound that significantly affects blood stage parasitemia and transmission of murine malaria and also inhibits Plasmodium falciparum growth in vitro. Here we show that treatment of Plasmodium berghei sporozoites with centanamycin impaired parasite function both in vitro and in vivo. The infection of hepatocytes by sporozoites in vitro was significantly reduced, and treated parasites showed arrested liver stage development. Inoculation of mice with sporozoites that were treated in vitro with centanamycin failed to produce blood stage infections. Furthermore, BALB/c and C57BL/6 mice vaccinated with treated sporozoites were protected against subsequent challenge with wild-type sporozoites. Our findings demonstrate that chemically attenuated sporozoites could be a viable alternative for the production of an effective liver stage vaccine for malaria.

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Evaluation of antimalarial prescription pattern and susceptibility of Plasmodium falciparum isolates in Kaduna, Nigeria

International Journal of Biological and Chemical Sciences ◽

10.4314/ijbcs.v13i7.34 ◽

2020 ◽

Vol 13 (7) ◽

pp. 3398-3410

Author(s):

O. Ifeoluwa Akanni ◽

J.O. Ehinmidu ◽

R.O. Bolaji

Keyword(s):

Plasmodium Falciparum ◽

Combination Therapy ◽

Antimalarial Drug ◽

Drug Prescription ◽

Artemisinin Combination Therapy ◽

Therapy Resistance ◽

Antimalarial Drugs ◽

In Vitro Susceptibility

Nigeria carries the highest burden of malaria in terms of morbidity and mortality. This is compounded by continuous resistance of Plasmodium falciparum to antimalarial drugs. This study was designed to evaluate the profile of malaria patients’ antimalarial drug prescription and in vitro susceptibility of P. falciparum isolates to commonly prescribed antimalarial drugs in Kaduna, Nigeria. Three years’ records of patients antimalarial drug prescriptions were collated (2013 to 2015) and the in vitro antimalarial agent susceptibility was determined for 28 clinical isolates using WHO Mark III microtest. Artemisinin-based combination therapy (ACT) was the most prescribed antimalarial for the period under review (92.3-93.7%). Among the ACTs, Artemether-lumefantrine was most prescribed. Of the 28 P. falciparum isolates evaluated, 3 (10.71%) were resistant to chloroquine with a median IC50 of 4.82μM (4.60-8.14μM), while five (17.86%) were resistant to mefloquine with a median IC50 of 25μM (10.3-41μM), 7(25.00%) to artemether with a median IC50 of 2.69μM (2.09-8.77μM), 9 (32.14%) to artesunate-mefloquine combination with a median IC50 of 9.0μM (7.98-35μM) and to artesunate, 11(39.29%) were resistant with a median IC50 of 2.4μM (1.56-5.65μM). This result shows a decline in resistance of P. falciparum to chloroquine compared to period prior to artemisinin-combination therapy as well as reduced susceptibility to artesunate and artemether. Further in vitro and in vivo monitoring will be required to inform antimalarial drug policy change.Keywords: Antimalarial, Artemisinin-combination therapy, resistance, susceptibility, microtest.

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Antimalarial Activity of Aqueous and 80% Methanol Crude Seed Extracts and Solvent Fractions of Schinus molle Linnaeus (Anacardiaceae) in Plasmodium berghei-Infected Mice

Journal of Tropical Medicine ◽

10.1155/2020/9473250 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Getu Habte ◽

Teshome Nedi ◽

Solomon Assefa

Keyword(s):

Acute Toxicity ◽

Plasmodium Berghei ◽

Antimalarial Activity ◽

Antimalarial Drugs ◽

Negative Control ◽

Aqueous Fraction ◽

Schinus Molle ◽

Crude Extracts

Background. Malaria is among the leading causes of mortality and morbidity. Moreover, the emergence of resistance to antimalarial drugs is a major problem in controlling the disease. This makes the development of novel antimalarial drugs a necessity. Medicinal plants are important sources in discovering antimalarial drugs. Schinus molle is claimed for its antimalarial effect in Ethiopian folkloric medicine and endowed with in vitro antiplasmodial activity. In the present study, the in vivo antimalarial activity of the plant was investigated. Methods. Acute toxicity was carried out using a standard procedure. To screen the in vivo antimalarial potential of the S. molle against Plasmodium berghei (ANKA), a 4-day suppressive test was employed. The extracts and fractions were given to infected mice by oral gavage at 100, 200, and 400 mg/kg/day for four consecutive days. Parameters such as parasitemia were then evaluated. Results. Any sign of toxicity was not observed in the oral acute toxicity test. The crude extracts and solvent fractions exerted a significant (p<0.05) inhibition of parasite load compared to the negative control. The highest inhibition (66.91%) was exhibited by the 400 mg/kg/day dose of 80% methanolic crude extract. Among the fractions, chloroform fraction demonstrated maximal chemosuppressive effect (55.60%). Moreover, crude extracts and solvent fractions prevented body weight loss, reduction in temperature, and anemia compared to the negative control. Except the aqueous fraction, the tested plant extracts were able to significantly prolong the survival time of infected mice. Conclusion. The findings of the present study confirmed the safety and a promising in vivo antimalarial activity of S. molle, thus supporting the traditional claim and in vitro efficacy. In-depth investigations on the plant, however, are highly recommended.

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