Plasmodium Falciparum 3D7 Research Articles

Rapid loss of group 1 innate lymphoid cells during blood stage Plasmodium infection.

ObjectivesInnate lymphoid cells (ILCs) share many characteristics with CD4+ T cells, and group 1 ILCs share a requirement for T‐bet and the ability to produce IFNγ with T helper 1 (Th1) cells. Given this similarity, and the importance of Th1 cells for protection against intracellular protozoan parasites, we aimed to characterise the role of group 1 ILCs during Plasmodium infection.MethodsWe quantified group 1 ILCs in peripheral blood collected from subjects infected with with Plasmodium falciparum 3D7 as part of a controlled human malaria infection study, and in the liver and spleens of Pc AS‐infected mice. We used genetically‐modified mouse models, as well as cell‐depletion methods in mice to characterise the role of group 1 ILCs during Pc AS infection.ResultsIn a controlled human malaria infection study, we found that the frequencies of circulating ILC1s and NK cells decreased as infection progressed but recovered after volunteers were treated with antiparasitic drug. A similar observation was made for liver and splenic ILC1s in P. chabaudi chabaudi AS (Pc AS)‐infected mice. The decrease in mouse liver ILC1 frequencies was associated with increased apoptosis. We also identified a population of cells within the liver and spleen that expressed both ILC1 and NK cell markers, indicative of plasticity between these two cell lineages. Studies using genetic and cell‐depletion approaches indicated that group 1 ILCs have a limited role in antiparasitic immunity during Pc AS infection in mice.DiscussionOur results are consistent with a previous study indicating a limited role for natural killer (NK) cells during Plasmodium chabaudi infection in mice. Additionally, a recent study reported the redundancy of ILCs in humans with competent B and T cells. Nonetheless, our results do not rule out a role for group 1 ILCs in human malaria in endemic settings given that blood stage infection was initiated intravenously in our experimental models, and thus bypassed the liver stage of infection, which may influence the immune response during the blood stage.ConclusionOur results show that ILC1s are lost early during mouse and human malaria, and this observation may help to explain the limited role for these cells in controlling blood stage infection.

Synthesis of Thymoquinone-Artemisinin Hybrids: New Potent Antileukemia, Antiviral, and Antimalarial Agents.

A series of hybrid compounds based on the natural products artemisinin and thymoquinone was synthesized and investigated for their biological activity against the malaria parasite Plasmodium falciparum 3D7 strain, human cytomegalovirus (HCMV), and two leukemia cell lines (drug-sensitive CCRF-CEM and multidrug-resistant subline CEM/ADR5000). An unprecedented one-pot method of selective formation of C-10α-acetate 14 starting from a 1:1 mixture of C-10α- to C-10β-dihydroartemisinin was developed. The key step of this facile method is a mild decarboxylative activation of malonic acid mediated by DCC/DMAP. Ether-linked thymoquinone-artemisinin hybrids 6a/b stood out as the most active compounds in all categories, while showing no toxic side effects toward healthy human foreskin fibroblasts and thus being selective. They exhibited EC50 values of 0.2 μM against the doxorubicin-sensitive as well as the multidrug-resistant leukemia cells and therefore can be regarded as superior to doxorubicin. Moreover, they showed to be five times more active than the standard drug ganciclovir and nearly eight times more active than artesunic acid against HCMV. In addition, hybrids 6a/b possessed excellent antimalarial activity (EC50 = 5.9/3.7 nM), which was better than that of artesunic acid (EC50 = 8.2 nM) and chloroquine (EC50 = 9.8 nM). Overall, most of the presented thymoquinone-artemisinin-based hybrids exhibit an excellent and broad variety of biological activities (anticancer, antimalarial, and antiviral) combined with a low toxicity/high selectivity profile.

SYNTHESIS OF 2-HIDROXYXANTHONE FROM XANTHONE AS A BASIC MATERIAL FOR NEW ANTIMALARIAL DRUGS

Objective: The purpose of this research is to synthesize 2-hydroxyxanthone from xanthone and to evaluate its antiplasmodial activity.Methods: The synthesis of 2-hydroxyxanthone followed the sequence of these synthetic stages, namely: 2-nitroxanthone, 2-aminoxanthone, and 2-hydroxyxanthone. The products were separated by chromatography methods including thin layer chromatography and vacuum liquid chromatography. Compound structures of the isolated products were determined based on their infrared and nuclear magnetic resonance spectra. To support these findings, the spectra were also matched to the corresponding data from literatures. The biological properties of the synthetic compound were evaluated toward Plasmodium falciparum 3D7.Results: 2-nitroxanthone was obtained as a brownish-yellow crystal in 69.00% yield with Madhya Pradesh of 181°C. Reduction of 2-nitroxanthone using SnCl2.2H2O/hydrogen chloride produced 2-aminoxanthone as a pale-yellow solid in 60.60% yield. Finally, the desired 2-hydroxyxanthone was achieved by initially reacting 2-aminoxanthone with sodium nitride to produce diazonium salt. Then, hydrolysis of the salt yielded 2-hydroxyxanthone as a white solid in 69.81% yield. Synthesis of 2-hydroxyxanthone from xanthone had an overall yield of38.35%. In vitro antiplasmodial assay against P. falciparum 3D7 showed that the half maximal inhibitory concentration value was 0.44 μg/mL.Conclusions: An antimalarial compound (2-hydroxyxanthone) was successfully synthesized from xanthone in three steps of synthetic reactions, i.e., the formation of 2-nitroxanthone, 2-aminoxanthone, and 2-hydroxyxanthone.

Design, synthesis, conformational and molecular docking study of some novel acyl hydrazone based molecular hybrids as antimalarial and antimicrobial agents

BackgroundAcyl hydrazones are an important class of heterocyclic compounds promising pharmacological characteristics. Malaria is a life-threatening mosquito-borne blood disease caused by a plasmodium parasite. In some places, malaria can be treated and controlled with early diagnosis. However, some countries lack the resources to do this effectively.ResultsThe present work involves the design and synthesis of some novel acyl hydrazone based molecular hybrids of 1,4-dihydropyridine and pyrazole (5a–g). These molecular hybrids were synthesised by condensation of 1,4-dihydropyridin-4-yl-phenoxyacetohydrazides with differently substituted pyrazole carbaldehyde. The final compound (5) showed two conformations (the major, E, s-cis and the minor, E, s-trans) as revealed by NMR spectral data and further supported by the energy calculations (MOPAC2016 using PM7 method). All the synthesised compounds were screened for their in vitro antimalarial activities against chloroquine-sensitive malaria parasite Plasmodium falciparum (3D7) and antimicrobial activity against Gram positive bacteria i.e. Bacillus cereus, Gram negative bacteria i.e. Escherichia coli and antifungal activity against one fungus i.e. Aspergillus niger. All these compounds were found more potent than chloroquine and clotrimazole, the standard drugs.ConclusionsIn vitro antiplasmodial IC50 value of the most potent compound 5d was found to be 4.40 nM which is even less than all the three reference drugs chloroquine (18.7 nM), pyrimethamine (11 nM) and artimisinin (6 nM). In silico binding study of compound 5d with plasmodial cysteine protease falcipain-2 indicated the inhibition of falcipain-2 as the probable reason for the antimalarial potency of compound 5d. All the compounds had shown good to excellent antimicrobial and antifungal activities.

Exploring Heme and Hemoglobin Binding Regions of Plasmodium Heme Detoxification Protein for New Antimalarial Discovery.

Hemoglobin degradation/hemozoin formation, essential steps in the Plasmodium life cycle, are targets of existing antimalarials. The pathway still offers vast possibilities to be explored for new antimalarial discoveries. Here, we characterize heme detoxification protein, PfHDP, a major protein involved in hemozoin formation, as a novel drug target. Using in silico and biochemical approaches, we identified two heme binding sites and a hemoglobin binding site in PfHDP. Treatment of Plasmodium falciparum 3D7 parasites with peptide corresponding to the hemoglobin binding domain in PfHDP resulted in food vacuole abnormalities similar to that seen with a cysteine protease inhibitor, E-64 (I-1). Screening of compounds that bound the modeled PfHDP structure in the heme/hemoglobin-binding pockets from Maybridge Screening Collection identified a compound, ML-2, that inhibited parasite growth in a dose-dependent manner, thus paving the way for testing its potential as a new drug candidate. These results provide functional insights into the role of PfHDP in Hz formation and further suggest that PfHDP could be an important drug target to combat malaria.

Wakodecalines A and B, new decaline metabolites isolated from a fungus Pyrenochaetopsis sp. RK10-F058.

Two new decaline metabolites, wakodecalines A and B, were isolated from a fungus, Pyrenochaetopsis sp. RK10-F058, by screening for structurally unique metabolites using LC/MS analysis. Their structures were determined on the basis of NMR and mass spectrometric measurements. The absolute structures were confirmed by a combination of chemical methods including chemical degradation, a modified Mosher's method and Marfey's method, and comparison of the experimental electronic CD (ECD) spectrum with calculated one. Both compounds had a cyclopentanone-fused decaline skeleton and an N-methylated amino acid moiety derived from a serine. They showed moderate antimalarial activity against the Plasmodium falciparum 3D7 strain.The Journal of Antibiotics advance online publication, 13 September 2017; doi:10.1038/ja.2017.103.

RETRACTED ARTICLE: Antimalarial efficacy of Pongamia pinnata (L) Pierre against Plasmodium falciparum (3D7 strain) and Plasmodium berghei (ANKA)

BackgroundThe objective of the current study was to assess the in vitro antiplasmodial activities of leaf, bark, flower, and the root of Pongamia pinnata against chloroquine-sensitive Plasmodium falciparum (3D7 strain), cytotoxicity against Brine shrimp larvae and THP-1 cell line. For in vivo study, the plant extract which has shown potent in vitro antimalarial activity was tested against Plasmodium berghei (ANKA strain).MethodsThe plant Pongamia pinnata was collected from the herbal garden of Acharya Nagarjuna University of Guntur district, Andhra Pradesh, India. Sequentially crude extracts of methanol (polar), chloroform (non-polar), hexane (non-polar), ethyl acetate (non-polar) and aqueous (polar) of dried leaves, bark, flowers and roots of Pongamia pinnata were prepared using Soxhlet apparatus. The extracts were screened for in vitro antimalarial activity against P. falciparum 3D7 strain. The cytotoxicity studies of crude extracts were conducted against Brine shrimp larvae and THP-1 cell line. Phytochemical analysis of the plant extracts was carried out by following the standard methods. The chemical injury to erythrocytes due to the plant extracts was checked. The in vivo study was conducted on P. berghei (ANKA) infected BALB/c albino mice by following 4-Day Suppressive, Repository, and Curative tests.ResultsOut of all the tested extracts, the methanol extract of the bark of Pongamia pinnata had shown an IC50 value of 11.67 μg/mL with potent in vitro antimalarial activity and cytotoxicity evaluation revealed that this extract was not toxic against Brine shrimp and THP-1 cells. The injury to erythrocytes analysis had not shown any morphological alterations and damage to the erythrocytes after 48 h of incubation. Because methanolic bark extract of Pongamia pinnata has shown good antimalarial activity in vitro, it was also tested in vivo. So the extract had exhibited an excellent activity against P. berghei malaria parasite while decrement of parasite counts was moderately low and dose-dependent (P < 0.05) when compared to the control groups, which shown a daily increase of parasitemia, unlike the CQ-treated groups. The highest concentration of the extract (1000 mg/kg b.wt./day) had shown 83.90, 87.47 and 94.67% of chemo-suppression during Suppressive, Repository, and Curative tests respectively which is almost nearer to the standard drug Chloroquine (5 mg/kg b.wt./day). Thus, the study has revealed that the methanolic bark extract had shown promisingly high ((P < 0.05) and dose-dependent chemo-suppression. The phytochemical screening of the crude extracts had shown the presence of alkaloids, flavonoids, triterpenes, tannins, carbohydrates, phenols, coumarins, saponins, phlobatannins and steroids.ConclusionsThe present study is useful to develop new antimalarial drugs in the scenario of the growing resistance to the existing antimalarials. Thus, additional research is needed to characterize the bioactive molecules of the extracts of Pongamia pinnata that are responsible for inhibition of malaria parasite.

Skrining Aktivitas Antimalaria Beberapa Tanaman Indonesia Hasil Eksplorasi Dari Hutan Raya Cangar, Batu-Malang, Jawa Timur

Background: Malaria is the most important parasitic disease. Malaria control which depends on specific chemotherapy now complicated by resistance of Plasmodium falciparum to most commonly available antimalarial drug. Such situation has heralded the need for alternative antimalarial therapy. Objective: This research aim was to find new antimalarial candidates from some Indonesia plants collected from Cangar National Forest, Batu-Malang, East Java. Methods: Eleven samples of leaves and stem extracts were screened against Plasmodium falciparum 3D7 culture which maintained in RPMI-1640 Medium. Samples tested in concentration of 0.01, 0.1, 1, 10 and 100 µg/ml. Probit analysis was used to determine IC50. Results: In vitro antimalarial activity revealed that only three crude extracts samples from Fraxinus griffithi stem extract, Piper sulcatum leaves extract and Eucalyptus globulus stem extract had good antimalarial activity with IC50 value of 0.33, 0.20 and 0.55 µg/ml, respectively. Conclusions: Fraxinus griffithi stem extract, Piper sulcatum leaves extract and Eucalyptus globulus stem extract might be a good candidate for antimalarial natural product resources.

Skrining Aktivitas Antimalaria Beberapa Tanaman Indonesia Hasil Eksplorasi Dari Hutan Raya Cangar, Batu-Malang, Jawa Timur

Background: Malaria is the most important parasitic disease. Malaria control which depends on specific chemotherapy now complicated by resistance of Plasmodium falciparum to most commonly available antimalarial drug. Such situation has heralded the need for alternative antimalarial therapy. Objective: This research aim was to find new antimalarial candidates from some Indonesia plants collected from Cangar National Forest, Batu-Malang, East Java. Methods: Eleven samples of leaves and stem extracts were screened against Plasmodium falciparum 3D7 culture which maintained in RPMI-1640 Medium. Samples tested in concentration of 0.01, 0.1, 1, 10 and 100 µg/ml. Probit analysis was used to determine IC50. Results: In vitro antimalarial activity revealed that only three crude extracts samples from Fraxinus griffithi stem extract, Piper sulcatum leaves extract and Eucalyptus globulus stem extract had good antimalarial activity with IC50 value of 0.33, 0.20 and 0.55 µg/ml, respectively. Conclusions: Fraxinus griffithi stem extract, Piper sulcatum leaves extract and Eucalyptus globulus stem extract might be a good candidate for antimalarial natural product resources.

Evaluation of antiplasmodial properties of a cyanobacterium, Spirulina platensis and its mechanism of action

The rapid emergence of antimalarial drug resistance necessitates a continual effort on novel drug discovery. A cyanobacterium, Spirulina platensis, is a potential antimalarial agent that has been widely consumed as food supplement in the form of crude extract. It is known to possess antiviral, antibacterial and antifungi activities. This study examined the antimalarial activities of several Spirulina formulas against Plasmodium falciparum 3D7, in vitro. The tested Spirulina formulas included commercially available capsule, crude extract and alkaloid fraction. Results showed that all tested formula possessed antimalarial activities with the Spirulina capsule exhibited the highest activities (IC50 = 2.16 μg/mL). Light and electron microscopies revealed interference of the Spirulina with the parasite hemozoin formation. In conclusion, all tested Spirulina formulas and fraction exhibited moderate to high antimalarial activities.

Chalcone analogue as potent anti-malarial compounds against Plasmodium falciparum: Synthesis, biological evaluation, and docking simulation study

ObjectiveTo investigate in vitro antimalarial activity of chalcone derivative compounds against Plasmodium falciparum 3D7 (Pf3D7) strain and in silico antimalarial activity. MethodsSynthesis of the chalcone derivatives was conducted via Claisen-Schmidt method using NaOH 60% base as catalyst. An in vitro antimalarial activity assay was carried out according to the Rieckmann method against the chloroquine-sensitive Pf3D7 strain. Molecular docking studies of the prepared compounds were performed using Discovery Studio 3.1 (Accelrys, Inc., San Diego, USA) software to dihydrofolate reductases–thymidylate synthase (PfDHFR-TS) protein with Protein Data Bank ID of 1J3I.pdb (sensitive-protein) and ID: 4DP3.pdb (resistance-protein). ResultsThis work has successfully synthesized seven chalcone derivatives with a great antimalarial activity. It has been revealed that allyloxy, hydroxy and alkoxy functional groups could increase the antimalarial activity of the chalcone derivatives. The best antimalarial activity of the prepared compounds was possessed by 3b with an IC50 value of 0.59 μM and categorized as an excellent antiplasmodial. Molecular docking studies of 3b showed binding interaction with the amino acid residues such as Ala16, Ile164, Phe58, Tyr170 of the 1J3I.pdb protein and also Ala16, Phe58, Ile112, Met55 of the 4DP3.pdb protein. ConclusionsAn in vitro antimalarial assay of the prepared chalcone derivative (3a–g) showed an excellent and good antiplasmodial activity against the chloroquine-sensitive Pf3D7 strain. In silico antimalarial studies revealed that 3a–g made binding interaction with both sensitive-protein (1J3I.pdb) and resistance-protein (4DP3.pdb), which means that they were both active against chloroquine-sensitive and resistant plasmodium strain.

Isolation and structure elucidation of halymeniaol, a new antimalarial sterol derivative from the red alga Halymenia floresii

A new mono-hydroxy acetylated sterol derivative: 12β-hydroxy-3β, 15α, 16β-triacetoxy-cholest-5-en-7-one (halymeniaol) (1), and cholesterol (2) were isolated from the marine red alga Halymenia floresii. The structure of the compound 1 (halymeniaol) was established from its spectral data, derived from HRMS/MS and 2D NMR. Compound 1 exhibited growth inhibitory activity against chloroquine-resistant Plasmodium falciparum 3D7 strain with an IC50 of 3.0 μM.

Synthesis of Novel Hybrids of Quinazoline and Artemisinin with High Activities against Plasmodium falciparum, Human Cytomegalovirus, and Leukemia Cells.

Many quinazoline derivatives have been synthesized over the last few decades with great pharmacological potential, such as antimalarial, anti-inflammatory, antimicrobial, anticancer, and antiviral. But so far, no quinazoline–artemisinin hybrids have been reported in the literature. In the present study, five novel quinazoline–artemisinin hybrids were synthesized and evaluated for their in vitro biological activity against malarial parasites (Plasmodium falciparum 3D7), leukemia cells (CCRF-CEM and CEM/ADR5000), and human cytomegalovirus. Remarkably, hybrid 9 (EC50 = 1.4 nM), the most active antimalarial compound of this study, was not only more potent than artesunic acid (EC50 = 9.7 nM) but at the same time more active than the clinically used drugs dihydroartemisinin (EC50 = 2.4 nM) and chloroquine (EC50 = 9.8 nM). Furthermore, hybrids 9 and 10 were the most potent compounds with regard to anticytomegaloviral activity (EC50 = 0.15–0.21 μM). They were able to outperform ganciclovir (EC50 = 2.6 μM), which is the relevant standard drug of antiviral therapy, by a factor of 12–17. Moreover, we identified a new highly active quinazoline derivative, compound 14, that is most effective in suppressing cytomegalovirus replication with an EC50 value in the nanomolar range (EC50 = 50 nM). In addition, hybrid 9 exhibited an antileukemia effect similar to that of artesunic acid, with EC50 values in the low micromolar range, and was 45 times more active toward the multidrug-resistant CEM/ADR5000 cells (EC50 = 0.5 μM) than the standard drug doxorubicin.

Antibody-dependent NK cell control of Plasmodium falciparum infection

Abstract Plasmodium falciparum (P.f) infection is a major cause of morbidity and mortality world-wide where symptoms and death occur as a result of the blood stage of the P.f. life cycle. To date, there is no effective blood stage malarial vaccine. Natural Killer (NK) cells are key players in the control of hematopoietic cancers and viral infections, however their role in blood stage malaria is unknown. We undertook a comprehensive analysis of NK cell phenotype and function in a cohort of subjects from a malaria clinical study in Mali, Africa. Using an unbiased analysis of different NK cell subsets, we found that ‘adaptive’ NK cells (lacking FcR gamma chain) increased with age and correlated with reduced malaria risk. Adaptive NK cells had enhanced antibody dependent cellular cytotoxicity (ADCC) function relative to other NK cell subsets. Antibodies are known to be protective in malaria, however the mechanism of this protection is still being elucidated. We hypothesized the protective mechanism of adaptive NK cells may be adaptive NK cells pairing with malaria antibodies to clear infected RBCs via ADCC. In a parallel study, we have shown that NK cells from healthy US donors can inhibit the growth of Plasmodium falciparum 3D7 strain in vitro in the presence of IgG from malaria-exposed adults. Adaptive NK cells from Mali also have enhanced ADCC to infected RBCs. This work indicates that protective antibodies may pair with the strong ADCC activity of adaptive NK cells to protect human subjects from malaria symptoms. These findings thus open a new avenue for vaccine development exploring antibody-dependent cell mediated killing of malaria parasites.

Anti-Plasmodial Assessment of Four Different Iranian Propolis Extracts.

Eradication of malaria will depend on discovery of new intervention tools such as anti-malarial drugs. Due to the increasing interest in the application of propolis against significant clinical pathogenic agents, the aim of the present investigation was to evaluate the anti-plasmodial effect of Iranian propolis extracts against chloroquine (CQ)-sensitive Plasmodium falciparum 3D7 and Plasmodium berghei (ANKA strain). Crude samples of honeybee (Apis mellifera) propolis were collected from four provinces in northern (Kalaleh, Golestan), northeastern (Chenaran, Razavi Khorasan), central (Taleghan, Alborz) and western (Morad Beyg, Hamedan) areas of Iran with different types of flora. The dried propolis samples were extracted with three different solvents, including ethanol 70% (EtOH), ethyl acetate (EA) and dichloromethane (DCM). All extracts were shown to have in vitro anti-plasmodial activity with IC50 ranging from 16.263 to 80.012 µg/mL using parasite lactate dehydrogenase (pLDH) assay. The DCM extract of Morad Beyg propolis indicated the highest anti-plasmodial activity (IC50: 16.263 ± 2.910 μg/mL; P = 0.027, Kruskal-Wallis H-test). The samples were also evaluated in mice for their in vivo anti-plasmodial effect. The curative effect against established infection (Rane test) showed that both extracts at all doses (50, 100, and 200 mg/kgBW) produced anti-plasmodial activity against the parasite. Furthermore, using gas chromatography-mass spectrometry (GC-MS), the quantity of flavonoids in DCM and EtOH 70% extracts were found to be 7.42% and 3.10%, respectively. The potent anti-plasmodial activity of both EtOH 70% and DCM extracts of the propolis of Morad Beyg, Hamedan suggests further analyses of individual components to assess its utilization as anti-malarial drugs.

Deeper Insight into the Six‐Step Domino Reaction of Aldehydes with Malononitrile and Evaluation of Antiviral and Antimalarial Activities of the Obtained Bicyclic Products

The straightforward and efficient synthesis of complex aza‐ and carbobicyclic compounds, which are of importance for medicinal chemistry, is a challenge for modern chemical methodology. An unprecedented metal‐free six‐step domino reaction of aldehydes with malononitrile was presented in our previous study to provide, in a single operation, these bicyclic nitrogen‐containing molecules. Presented here is a deeper investigation of this atom‐economical domino process by extending the scope of aldehydes, performing post‐modifications of domino products, applying bifunctional organocatalysts and comprehensive NMR studies of selected domino products. The thermodynamic aspects of the overall reaction are also demonstrated using DFT methods in conjunction with a semi‐empirical treatment of van der Waals interactions. Furthermore, biological studies of seven highly functionalized and artemisinin‐containing domino products against human cytomegalovirus (HCMV) and Plasmodium falciparum 3D7 are presented. Remarkably, in vitro tests against HCMV revealed five domino products to be highly active compounds (EC50 0.071–1.8 μm), outperforming the clinical reference drug ganciclovir (EC50 2.6 μm). Against P. falciparum 3D7, three of the investigated artemisinin‐derived domino products (EC50 0.72–1.8 nm) were more potent than the clinical drug chloroquine (EC50 9.1 nm).

Ferrocenyl and organic novobiocin derivatives: Synthesis and their in vitro biological activity

A focused series of novobiocin derivatives containing a ferrocene unit together with their corresponding organic novobiocin analogues have been synthesized in modest to good yields. These compounds were screened for biological activity against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) and human breast cancer cell line (HCC38). With the exception of compounds 5c and 5d, the general trend observed is that incorporation of the ferrocene moiety into novobiocin scaffold resulted in compounds 6a–d/6f showing enhanced activity compared to organic analogues 5a–b and 5e–f.

Novel carbazole aminoalcohols as inhibitors of β-hematin formation: Antiplasmodial and antischistosomal activities

Malaria and schistosomiasis are two of the most socioeconomically devastating parasitic diseases in tropical and subtropical countries. Since current chemotherapeutic options are limited and defective, there is an urgent need to develop novel antiplasmodials and antischistosomals. Hemozoin is a disposal product formed from the hemoglobin digestion by some blood-feeding parasites. Hemozoin formation is an essential process for the parasites to detoxify free heme, which is a reliable therapeutic target for identifying novel antiparasitic agents. A series of novel carbazole aminoalcohols were designed and synthesized as potential antiplasmodial and antischistosomal agents, and several compounds showed potent in vitro activities against Plasmodium falciparum 3D7 and Dd2 strains and adult and juvenile Schistosoma japonicum. Investigations on the dual antiparasitic mechanisms showed the correlation between inhibitory activity of β-hematin formation and antiparasitic activity. Inhibiting hemozoin formation was identified as one of the mechanisms of action of carbazole aminoalcohols. Compound 7 displayed potent antiplasmodial (Pf3D7 IC50 = 0.248 μM, PfDd2 IC50 = 0.091 μM) and antischistosomal activities (100% mortality of adult and juvenile schistosomes at 5 and 10 μg/mL, respectively) and exhibited low cytotoxicity (CC50 = 7.931 μM), which could be considered as a promising lead for further investigation. Stoichiometry determination and molecular docking studies were also performed to explain the mode of action of compound 7.

Antiplasmodial activity of Mezoneuron benthamianum leaves and identification of its active constituents

Ethnopharmacological relevanceDecoctions of the leaves of M. benthamianum Baill. are used by traditional healers in Guinea to treat malaria and this use was validated by a preliminary clinical assay. Aim of the studyTo evaluate the in vitro antiplasmodial activity and to identify active compounds from extracts of M. benthamianum leaves. Material and methodsAntiplasmodial activity of extracts, fractions and pure compounds was evaluated in vitro against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) using the measurement of the plasmodial lactate dehydrogenase activity. Selectivity of extracts and purified compounds for Plasmodium parasites was evaluated by using WST-1 test on HeLa human cells. Compounds were isolated using normal phase silica gel column chromatography and prepHPLC and their structures elucidated using extensive spectroscopic analysis. ResultsHydroethanolic extracts (70% v/v) of M. benthamianum leaves showed a moderate in vitro activity against P. falciparum 3D7, with IC50 in the range 22.5 – 32.6µg/mL, depending on the batch; while a dark precipitate formed during ethanol evaporation showed higher activity (IC50 =6.5µg/mL). The fractionation was performed on this most active fraction and was followed by in vitro antiplasmodial assay. Active compounds (5, 7, 8) belong to several phytochemical classes, contributing together to the global antiplasmodial activity of the hydroethanolic extract against P. falciparum parasite. This study finally allowed the isolation of three diterpenes including two new compounds named Mezobenthamic acids A (1) and B (2) and neocaesalpin H (3), as well as quercetin (4), kaempferol (7), resveratrol (6), gallic acid (9) and its ethylester (5), β-sitosterol glucoside (10) and 13b-hydroxy-pheophorbide a (8). ConclusionThis study gives some concrete evidence to support the ethnopharmacological use of Mezoneuron benthamianum leaves extract in the management of malaria. The active compounds can be further studied for their antiplasmodial potential, as well as their suitability to be used as quality markers for the standardization of this herbal drug from the Guinean traditional pharmacopeia.

Antimalarial activity of Garcinia mangostana L rind and its synergistic effect with artemisinin in vitro

BackgroundMalaria especially falciparum malaria still causes high morbidity and mortality in tropical countries. Several factors have been linked to this situation and the most important one is the rapid spread of parasite resistance to the currently available antimalarials, including artemisinin. Artemisinin is the main component of the currently recommended antimalarial, artemisinin based combination therapy (ACT), and it is a free radical generating antimalarial. Garcinia mangostana L (mangosteen) rind contain a lot of xanthone compounds acting as an antioxidant and exhibited antimalarial activity. The aim of this study was to evaluate the antimalarial activity of mangosteen rind extract and its fractions and their interaction with artemisinin against the 3D7 clone of Plasmodium falciparum in vitro.MethodsDry ripe mangosteen rind was extracted with ethanol followed by fractionation with hexane, ethylacetate, buthanol, and water consecutively to get ethanol extract, hexane, athylacetate, buthanol, and water fractions. Each of these substances was diluted in DMSO and examined for antimalarial activity either singly or in combination with artemisinin in vitro against Plasmodium falciparum 3D7 clone. Synergism between these substances with artemisinin was evaluated according to certain formula to get the sum of fractional inhibitory concentration 50 (∑FIC50).ResultsAnalysis of the parasite growth in vitro indicated that IC50 of these mangosteen rind extract, hexane, ethylacetate, buthanol, and water fraction ranged from 0.41 to > 100 μg/mL. All of the ∑FIC50 were <1.ConclusionsThis study demonstrated a promising antimalarial activity of the extract and fractions of G.mangostana L rind and its synergistic effect with artemisinin. Further study using lead compound(s) isolated from extract and fractions should be performed to identify more accurately their mechanism of antimalarial activities.