Malarial Chemotherapy Research Articles

Current Trends in Nanotechnology-based Drug Delivery Systems for the Diagnosis and Treatment of Malaria: A Review.

Malaria is still a major endemic disease transmitted in humans via Plasmodium-infected mosquitoes. The eradication of malarial parasites and the control measures have been rigorously and extensively deployed by local and international health organizations. Malaria's recurrence is a result of the failure to entirely eradicate it. The drawbacks related to malarial chemotherapy, non-specific targeting, multiple drug resistance, requirement of high doses, intolerable toxicity, indefinable complexity of Plasmodium's life cycle, and advent of drug-resistant strains of P. falciparum are the causes of the ineffective eradication measures. With the emergence of nanotechnology and its application in various industrial domains, the rising interest in the medical field, especially in epidemiology, has skyrocketed. The applications of nanosized carriers have sparked special attention, aiming towards minimizing the overall side effects caused due to drug therapy and avoiding bioavailability. The applications of concepts of nanobiotechnology to both vector control and patient therapy can also be one of the approaches. The current study focuses on the use of hybrid drugs as next-generation antimalarial drugs because they involve fewer drug adverse effects. The paper encompasses the numerous nanosized delivery-based systems that have been found to be effective among higher animal models, especially in treating malarial prophylaxis. This paper delivers a detailed review of diagnostic techniques, various nanotechnology approaches, the application of nanocarriers, and the underlying mechanisms for the management of malaria, thereby providing insights and the direction in which the current trends are imparted from the innovative and technological perspective.

In vitro drug interaction of ionophores with artemisinin and chloroquine against Plasmodium falciparum 3D7 blood-stage infection

The prevalence of clinical resistance of P. falciparum towards artemisinin and its partner drugs has significantly hampered malarial chemotherapy. To circumvent this situation, identifying a new class of partner drugs with significant anti-malarial efficacy and multi-stage activity can slow the development of resistance. This study demonstrates the potential interactions of carboxylic ionophores such as monensin (MON), maduramicin (MAD) or salinomycin (SAL) with standard antimalarial drugs artemisinin (ART) or chloroquine (CQ). The in vitro drug interactions were studied in P. falciparum 3D7 strain by a growth inhibition SYBR green 1 assay. The asynchronized parasites were exposed for 48 h in the presence of varying proportions of two drug concentrations using the modified fixed-ratio isobologram method. We determined the growth inhibition response and the sums of the fractional inhibitory concentrations (ΣFICs) of the following drug combinations (4:1, 3:2, 2:3, 1:4) and (1:1, 1:3, 3:1) were calculated for 50% inhibitory concentrations (IC50s). Combining artemisinin with monensin, maduramicin, or salinomycin showed significant additive interaction. A combination of chloroquine with monensin, maduramicin, or salinomycin showed slight synergism to additive interaction. None of the drug combinations displayed an antagonistic effect indicating ionophores usage in combination therapy to treat drug-resistant malarial infections.

Key interactions of pyrimethamine derivatives specific to wild-type and mutant P. falciparum dihydrofolate reductase based on 3D-QSAR, MD simulations and quantum chemical calculations

Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is an important target enzyme in malarial chemotherapy. An understanding of how novel inhibitors interact with wild-type (wtPfDHFR), quadruple-mutant (qmPfDHFR), and human (hDHFR) enzymes is required for the development of these compounds as antimalarials. This study is focused on a series of des-Cl and m-Cl phenyl analogs of pyrimethamine with various flexible 6-substituents. The interactions of these compounds with DHFR enzymes were investigated by 3 D-QSAR, MD simulations, MM-PBSA, and DFT calculations. CoMFA and CoMSIA models were developed with good predictive abilities for wtPfDHFR and qmPfDHFR. For hDHFR, CoMSIA models combined with clogP descriptor were successfully derived. Binding free energy using MM-PBSA and comparison of per residue decomposition energy analyses with the DFT method at M06-2X/6-31G ++(d,p) level of theory indicated that Asp54 and Phe58 play important roles in the binding of the most potent compound in the series (compound 27) with both wtPfDHFR and qmPfDHFR, whereas Arg59 and Arg122 were additionally found to interact with this inhibitor in qmPfDHFR. For hDHFR, the residues Glu30 and Phe34 but not Arg70, equivalent to Asp54, Phe58, and Arg122 in PfDHFR, also play role in compound 27 binding through strong hydrophobic interactions (Phe34) and hydrogen bond network with Glu30, Ile7, and Val115. From the key interactions identified in the DHFR-inhibitor complexes, a general scheme is proposed for designing new inhibitors selective for PfDHFR that is important for the development of novel antifolate antimalarials. Communicated by Ramaswamy H. Sarma

Molecular Targets for Malarial Chemotherapy: A Review.

The malaria parasite resistance to the existing drugs is a serious problem to the currently used antimalarials and, thus, highlights the urgent need to develop new and effective anti-malarial molecules. This could be achieved either by the identification of the new drugs for the validated targets or by further refining/improving the existing antimalarials; or by combining previously effective agents with new/existing drugs to have a synergistic effect that counters parasite resistance; or by identifying novel targets for the malarial chemotherapy. In this review article, a comprehensive collection of some of the novel molecular targets has been enlisted for the antimalarial drugs. The targets which could be deliberated for developing new anti-malarial drugs could be: membrane biosynthesis, mitochondrial system, apicoplasts, parasite transporters, shikimate pathway, hematin crystals, parasite proteases, glycolysis, isoprenoid synthesis, cell cycle control/cycline dependent kinase, redox system, nucleic acid metabolism, methionine cycle and the polyamines, folate metabolism, the helicases, erythrocyte G-protein, and farnesyl transferases. Modern genomic tools approaches such as structural biology and combinatorial chemistry, novel targets could be identified followed by drug development for drug resistant strains providing wide ranges of novel targets in the development of new therapy. The new approaches and targets mentioned in the manuscript provide a basis for the development of new unique strategies for antimalarial therapy with limited off-target effects in the near future.

Antiplasmodial Anthraquinones from Medicinal Plants: The Chemistry and Possible Mode of Actions

Malaria killed nearly half a million people in 2015, and 70% of this victims were young children. Malarial chemotherapy makes use of several drugs, each with its own pharmacological limitations, and with parasite resistance being the most challenging. People of low income nations often rely on traditional medicine as a treatment due to limited access to modern healthcare services. Despite uncertainties present in the outcome of traditional medicine, ethnomedicine approach has yielded important lead candidates. The investigation of medicinal plants utilized in the malaria endemic region yielded many antiplasmodial compounds with anthraquinone moiety. This paper describes natural anthraquinones extracted from medicinal plants utilized in traditional medicine for the treatment of malaria. In addition, the insight on structure-activity relationship and their mode of actions are also elaborated.

4-aminoquinolines: An Overview of Antimalarial Chemotherapy

Malaria is a major health problem and Plasmodium falciparum strain resistance to existing antimalarials drugs made the current approach inadequate for treatment of malaria. Drug development directed against malaria is generally targeting blood schizonts. However, to prevent relapse, tissue schizontocides are recommended to clean residual infection in the tissues. In spite of the available drugs, malarial chemotherapy is still insufficient and therefore new strategies are being explored to fill the gaps. The new approaches are being used to generate new compounds as well as combinations of drugs for development of effective and safe antimalarial therapy. This review discusses the recent developments in 4-aminoquinoline derived new analogs and insight into design and development of new antimalarials.

Synthesis and in vitro evaluation of novel 8-aminoquinoline–pyrazolopyrimidine hybrids as potent antimalarial agents

In the search of novel chemotherapeutic agents for emerging drug resistant parasites, the hybridization approaches have successfully emerged as an efficient tool in malarial chemotherapy. Herein, a rational design and synthesis of novel 8-aminoquinoline and pyrazolopyrimidine hybrids and their antimalarial activity against wild type Plasmodium falciparum (Pf_NF54) and resistant strain (Pf_K1) is reported. The medicinal chemistry approach to expand the scope of this series resulted in an identification of potent compounds with nanomolar potency (best IC50 5–10nM). Systematic structure activity relationship (SAR) studies revealed that pyrazolopyrimidine and 8-aminoquinoline ring are essential for achieving good P. falciparum potency. The docking study revealed that the compound 6 can retain some of the critical interactions within pfDHODH drug target.

In vitro and in vivo anti-malarial activity of tigecycline, a glycylcycline antibiotic, in combination with chloroquine.

BackgroundSeveral antibiotics have shown promising anti-malarial effects and have been useful for malarial chemotherapy, particularly in combination with standard anti-malarial drugs. Tigecycline, a semi-synthetic derivative of minocycline with a unique and novel mechanism of action, is the first clinically available drug in a new class of glycylcycline antibiotics.MethodsTigecycline was tested in vitro against chloroquine (CQ)-sensitive (D6) and resistant strains (W2) of Plasmodium falciparum alone and in combination with CQ. Tigecycline was also tested in vivo in combination with CQ in Plasmodium berghei-mouse malaria model for parasitaemia suppression, survival and cure of the malaria infection.ResultsTigecycline was significantly more active against CQ-resistant (W2) than CQ-susceptible (D6) strain of P. falciparum. Tigecycline potentiated the anti-malarial action of CQ against the CQ-resistant strain of P. falciparum by more than seven-fold. Further, treatment of mice infected with P. berghei with tigecycline (ip) produced significant suppression in parasitaemia development and also prolonged the mean survival time. Treatment with as low as 3.7 mg/kg dose of tigecycline, once daily for four days, produced 77-91% suppression in parasitaemia. In vivo treatment with tigecycline in combination with subcurative doses of CQ produced complete cure in P. berghei-infected mice.ConclusionResults indicate prominent anti-malarial action of tigecycline in vitro and in vivo in combination with CQ and support further evaluation of tigecycline as a potential combination candidate for treatment of drug-resistant cases of malaria.

4-aminoquinoline based molecular hybrids as antimalarials: an overview.

In recent times, the novel concept of generating hybrid molecules by pharmacophoric hybridisation approach is fast becoming an alternative to other existing strategies of drug development. These hybrids also known as 'dual drugs' or 'double drugs' are especially found to be effective in overcoming drug resistance problems. Towards this end, a lot of effort has been put for generating 4-aminoquinoline based hybrid molecules as next generation antimalarial drugs effective in malarial chemotherapy. This short review deals about the recent advances carried in the field of 4-aminoquinoline based molecular hybrids as potential antimalarial agents. It also presents a brief and simplified story on the development of 4-aminoquinolines as a mainstay in malarial research programmes.

Review on in-vitro anti-Malarial activity of Natural β-carboline Alkaloids

Malaria is one of the major health problems in developing countries. It kills 1-2 million people every year and also it affects financial status of many countries. Developed resistance to aminoquinoline (chloroquine), quinoline methanols (Quinine, Mefloquine) created troubles in malarial chemotherapy and signs of appearance of resistance to artemisinin based combination therapy (ACT) created emergency to develop novel antimalarial agents with high efficacy before spreading of resistance to ACT. From the ages natural products played an important role in antimalarial therapy, identification of natural products, semisynthetic and synthetic analogs with potent antiplasmodium activity is one of the best methods to develop novel antimalarial agents. In this review, we are presenting the antimalarial activity of natural β-carboline alkaloids and special interest on manzamine alkaloids and their structure activity relationship.

Chalcones as an Emerging Lead Molecule for Antimalarial Therapy: A Review

Chalcones (1, 3, diaryl-2-propen-1-ones), are one of the plant secondary metabolite belonging to flavonoid family and has been widely explored in past decennium for its various pharmacological activities including antimalarial activity. Plasmodium aspartate proteases and cysteine proteases are the promising targets in malarial chemotherapy to overcome the drug resistance. Chalcones supposed to show antimalarial activity by inhibiting either Plasmodium aspartate proteases or cysteine proteases. This review covers the mechanism of action, previous reported studies showing antimalarial activity of natural and synthetic chalcones and its derivatives along with future prospects to fight against drug resistant malaria. These compounds provide an option of developing inexpensive, synthetic therapeutic antimalarial agents and may serve as lead compounds for development of drug in near future.

Protein-Ligand interaction studies on 2, 4, 6- trisubstituted triazine derivatives as anti-malarial DHFR agents using AutoDock.

The dihydrofolate reductase (DHFR) domain of P. falciparum is one of the few well defined targets in malarial chemotherapy. The enzyme catalyzes the nicotinamide adenine dinucleotide phosphate (NADPH) dependent reduction of dihydrofolate to tetrahydrofolate. Protein-ligand interactions were studied using DHFR protein 2BL9, extracted from PDB to evaluate the strength of affinity of various molecules towards ligand binding site and to study the extent of correlation between experimental values and computational dock scores. AutoDock runs resulted in binding energy scores from -7.14 to -10.72 kcal/mol. Among the five inhibitors (Bioorganic and Medicinal Chemistry Letters 15 2005 531-533) selected for docking studies, an excellent correlation was observed in all cases, for instance, experimentally reported most active molecule 2a (MIC: 1µg/ml) showed a high dock score (-10.72 kcal/mol) than the remaining inhibitors. Therefore, molecular docking using AutoDock suggests the importance of evaluating the prediction accuracy of various molecules as evidenced by a correlation coefficient of 0.961 between experimental activities and AutoDock binding energies.

Tetraoxanes: Synthetic and Medicinal Chemistry Perspective

The discovery of artemisinin from Chinese medicinal plant, Artemisia annua in 1971, opened a new era in the malarial chemotherapy. This discovery was the beginning of exploring peroxides as potential replacements for the traditional antimalarial drugs such as chloroquine and mefloquine. The structurally simple class of peroxides that emerged from these studies was the 1,2,4,5-tetraoxanes. This study describes the current status of tetraoxane-based antimalarials that show significant promises because of their artemisinin-like activity. Literature from 1999 has been critically reviewed and an attempt has been made to discuss various synthetic methods and structure-activity relationship study among the series of tetraoxane-based compounds. © 2010 Wiley Periodicals, Inc. Med Res Rev.

Chloroquine excretion in semen following antimalarial-drug administration.

The study described here was carried out to establish whether or not chloroquine was excreted in semen. Chloroquine was assayed in the semen of eight male volunteers (aged between 19 and 45 years) by a fluorimetric method before and after taking a total dose of 1.500 mg chloroquine base corresponding to the accepted dosage of the drug in malarial chemotherapy. Mean pre- and post-drug administration levels of 0.7 +/- 0.2 microM and 5.7 +/- 0.6 microM were obtained respectively, indicating a significant excretion of chloroquine in semen.

Current trends in malarial chemotherapy

Malaria is a tropical disease caused by the genus Plasmodium. The sexual stage of the plasmodium is carried by mosquito while the asexual stage is carried by man. Transmission from the mosquito to man is through mosquito bite. Commonly presented symptoms of malarial attack include fever, weakness, anorexia, and anaemia. Some complications such as convulsion (in children) and acute pulmonary edema are common. The conventional drugs used in malarial chemotherapy include, chloroquin, sulfadoxine/pyramethamine, quinine and primaquine. Newer drugs in use include artemisine and its derivatives (such as dihydroartemisinine, artesunate, artemether), halofantrine, atovaquine, malaria vaccines, and artemisinine combinations (such as artemether/lumenfantrine, artesunate/mefloquine). These newer drugs were developed based on some shortcomings of the conventional drugs such as drug resistance and unbearable side effects. Of all the drugs available for the first line treatment of malaria, the artemisinine combinations are the drugs of choice as they possess reduced recrudescence and relapse when given for 3 days. Some new combinations are still on trial and include fosmidomycin/clindamycin. Malaria vaccines which show some promising features are also still undergoing more trials.

Current trends in malarial chemotherapy

Malaria is a tropical disease caused by the genus Plasmodium. The sexual stage of the plasmodium is carried by mosquito while the asexual stage is carried by man. Transmission from the mosquito to man is through mosquito bite. Commonly presented symptoms of malarial attack include fever, weakness, anorexia, and anaemia. Some complications such as convulsion (in children) and acute pulmonary edema are common. The conventional drugs used in malarial chemotherapy include, chloroquin, sulfadoxine/pyramethamine, quinine and primaquine. Newer drugs in use include artemisine and its derivatives (such as dihydroartemisinine, artesunate, artemether), halofantrine, atovaquine, malaria vaccines, and artemisinine combinations (such as artemether/lumenfantrine, artesunate/mefloquine). These newer drugs were developed based on some shortcomings of the conventional drugs such as drug resistance and unbearable side effects. Of all the drugs available for the first line treatment of malaria, the artemisinine combinations are the drugs of choice as they possess reduced recrudescence and relapse when given for 3 days. Some new combinations are still on trial and include fosmidomycin/clindamycin. Malaria vaccines which show some promising features are also still undergoing more trials.

Antimalarial Activity in Tropical Plants: A Review

ABSTRACT In recent years, a large number of plants have been explored for their antimalarial potential. Active principles from these plants have been isolated and analyzed in detail. Except for artemisinin, none of the principles were near the effectiveness of the existing antimalarial drug quinine. Regarding artemisinin the yield and isolation again had a drawback. Due to drug resistance by the parasites against quinine and its derivatives, there exist lacunae in malarial chemotherapy. In the present review, a number of potential antimalarial plants explored in the last two decades have been brought out and a number of leads suggested on the basis of their antimalarial activities.

Erythrocyte G Protein as a Novel Target for Malarial Chemotherapy

BackgroundMalaria remains a serious health problem because resistance develops to all currently used drugs when their parasite targets mutate. Novel antimalarial drug targets are urgently needed to reduce global morbidity and mortality. Our prior results suggested that inhibiting erythrocyte Gs signaling blocked invasion by the human malaria parasite Plasmodium falciparum. Methods and FindingsWe investigated the erythrocyte guanine nucleotide regulatory protein Gs as a novel antimalarial target. Erythrocyte “ghosts” loaded with a Gs peptide designed to block Gs interaction with its receptors, were blocked in β-adrenergic agonist-induced signaling. This finding directly demonstrates that erythrocyte Gs is functional and that propranolol, an antagonist of G protein–coupled β-adrenergic receptors, dampens Gs activity in erythrocytes. We subsequently used the ghost system to directly link inhibition of host Gs to parasite entry. In addition, we discovered that ghosts loaded with the peptide were inhibited in intracellular parasite maturation. Propranolol also inhibited blood-stage parasite growth, as did other β2-antagonists. β-blocker growth inhibition appeared to be due to delay in the terminal schizont stage. When used in combination with existing antimalarials in cell culture, propranolol reduced the 50% and 90% inhibitory concentrations for existing drugs against P. falciparum by 5- to 10-fold and was also effective in reducing drug dose in animal models of infection.ConclusionsTogether these data establish that, in addition to invasion, erythrocyte G protein signaling is needed for intracellular parasite proliferation and thus may present a novel antimalarial target. The results provide proof of the concept that erythrocyte Gs antagonism offers a novel strategy to fight infection and that it has potential to be used to develop combination therapies with existing antimalarials.

Pharmacological properties of a new antimalarial bisthiazolium salt, T3, and a corresponding prodrug, TE3.

A new approach to malarial chemotherapy based on quaternary ammonium that targets membrane biogenesis during intraerythrocytic Plasmodium falciparum development has recently been developed. To increase the bioavailability, nonionic chemically modified prodrugs were synthesized. In this paper, the pharmacological properties of a bisthiazolium salt (T3) and its bioprecursor (TE3) were studied. Their antimalarial activities were determined in vitro against the growth of P. falciparum and in vivo against the growth of P. vinckei in mice. Pharmacokinetic evaluations were performed after T3 (1.3 and 3 mg/kg of body weight administered intravenously; 6.4 mg/kg administered intraperitoneally) and TE3 (1.5 and 3 mg/kg administered intravenously; 12 mg/kg administered orally) administrations to rats. After intraperitoneal administration, very low doses offer protection in a murine model of malaria (50% efficient dose [ED50] of 0.2 to 0.25 mg/kg). After oral administration, the ED50 values were 13 and 5 mg/kg for T3 and TE3, respectively. Both compounds exerted antimalarial activity in the low nanomolar range. After TE3 administration, rapid prodrug-drug conversion occurred; the mean values of the pharmacokinetic parameters for T3 were as follows: total clearance, 1 liter/h/kg; steady-state volume of distribution, 14.8 liters/kg; and elimination half-life, 12 h. After intravenous administration, T3 plasma concentrations increased in proportion to the dose. The absolute bioavailability was 72% after intraperitoneal administration (T3); it was 15% after oral administration (TE3). T3 plasma concentrations (8 nM) 24 h following oral administration of TE3 were higher than the 50% inhibitory concentrations for the most chloroquine-resistant strains of P. falciparum (6.3 nM).

Pharmacokinetics of the diastereomers of arteether, a potent antimalarial drug, in rats

The pharmacokinetics of alpha- and beta- diastereomers of arteether, a potent erythrocytic schizontocidal agent, and their active metabolite dihydroartemisinin were studied in male Sprague-Dawley rats after oral, intramuscular and intravenous administrations. Oral and intramuscular studies were carried out at three dose levels at 9, 17.5 and 30 mg kg(-1). The ratio of alpha- and beta-isomers was maintained at 30:70% w/w in the formulations used for the study. The average oral bioavailabilities of alpha-and beta-isomers, relative to intramuscular administration, were 9.6% and 3.8%, respectively, and the average in vivo alpha- to beta- ratio was 2.5. Following intravenous and intramuscular administrations the in vivo alpha- to beta- ratios were 0.7 and 0.9, respectively. The beta-isomer of arteether was characterized by a longer elimination half-life and a relatively larger volume of distribution than the alpha-isomer, suggesting that beta-arteether may be responsible for the prolonged in vivo schizontocidal activity. The alpha-isomer was absorbed rapidly after oral and intramuscular administrations and showed higher peak plasma concentrations but possessed a relatively shorter half-life. There was an apparent lack of linearity observed in terms of dose and AUCs for both alpha- and beta-arteether after oral and intramuscular administrations, suggesting nonlinear dose dependent pharmacokinetics at the dose levels studied. The rate and extent of conversion of arteether isomers to dihydroartemisinin was highest with oral and intravenous administration and least with intramuscular indicating that the intramuscular route of administration of the isomeric mixture may be more beneficial for malarial chemotherapy.