Moderate Antiplasmodial Activity Research Articles

Spirocyclic iridoid alkaloids from Plumeria rubra.

Plumerianoids A-D (1-4) with a new intact spirocyclic iridoid alkaloid skeleton, along with a new degraded alkaloid 8-epi-plumerianine (5), and a known one (6), were isolated and characterized from Plumeria rubra. The structure of 6 was revised as (8R,13S)-plumerianine. These alkaloids consist of three epimeric pairs (1/2, 3/4, and 5/6), exhibiting virtually identical NMR spectra within each pair. Furthermore, the electronic circular dichroism (ECD) curves of each epimeric pair are roughly mirror-like, reminiscent of enantiomers. This study calls for attention on the structural elucidation of special compound classes when the associated chiral centers are far away from the chromophores and/or at the terminal of the molecules. In addition, compound 3 exhibited moderate antiplasmodial activity.

Improved production of palitantin by design of experiments and semi-synthesis of palitantin derivatives for bioactivity assessment

A new method for the production and isolation of (+)-palitantin (1) is herein reported, from cultures of the fungal strain Penicillium sp. AMF1a. (+)-Palitantin was isolated in 160 mg/L yield, as an alternative procedure to obtain 1 at a larger scale. The complete spectroscopic characterization, including conformational analysis, is presented for (+)-palitantin (1) and for its derivatives 3-α-palitantol (2), 3-β-palitantol (3), (Z)-palinitrorin (4), (Z)-paliphenin (5), (Z)-palifluorin (6) and (E)-palifluorin (7). The absolute configuration of the palitantin portion was confirmed by X-ray analysis of compound 4. The (4-(trifluoromethyl)benzyl)-hydrazone derivatives (6 and 7) displayed moderate biological activities. (Z)-Palifluorin (6) exhibited moderate antiplasmodial activity, while (E)-palifluorin (7) displayed weak antibacterial activity against E. faecalis and S. aureus, while palitantin itself was inactive in the same bioassays, indicating that the semi-synthesis of nitrogenated derivatives of 1 may be of potential interest to generate bioactive palitantin derivatives.

In vitro evaluation of the antiplasmodial activity and phytochemical screening of five plants extracts from the traditional pharmacopoeia in Côte d'Ivoire

The resistance of Plasmodium falciparum to current antimalarial drugs, namely artemisinin derivatives associated with a partner molecule, requires the search for new therapeutic alternatives through traditional pharmacopoeia, rich in medicinal plants. The aim of this study is to assess the in vitro anti-plasmodial activity of leaf extracts from five plants selected for their traditional use against malaria. An ethnopharmacological survey was carried out in Agboville to identify plants traditionally used against malaria in this region. The leaves of these plants were harvested, dried and extracted using aqueous and hydroethanolic solvents. The extracts obtained were then subjected to an in vitro anti-plasmodial test using SYBR GREEN to assess their ability to inhibit the growth of Plasmodium falciparum. Phytochemical screening and high-performance liquid chromatography-mass spectrometry (LC-MS) was carried out to identify the chemical compounds present in the extracts. In total, ten extracts from the dried leaves of five plants were tested on clinical isolates of Plasmodium falciparum. Of these, only Momordica charantia extracts showed an IC50 ≤ 5 µg/ml, namely 1.93 µg/ml for the hydroethanolic extract and 4.35 µg/ml for the aqueous extract. The anti-plasmodial activity of these extracts was described as powerful. Extracts from other plants showed IC50 values ranging from 16.19 µg/ml to 31.43 µg/ml, indicating moderate anti-plasmodial activity. Phytochemical analyses mainly revealed the presence of flavonoids, alkaloids, polyterpenes and phenolic acids, suggesting that these compounds may be responsible for the anti-plasmodial activity observed. In conclusion, the search for natural products capable of blocking the transmission of malaria must be pursued with determination, and further studies are needed before the formulation of phytomedicines from these plants can be envisaged.

Characterization and Inhibition of the Chaperone Function of Plasmodium falciparum Glucose-Regulated Protein 94 kDa (PfGrp94).

Plasmodium falciparum expresses four heat shock protein 90 (Hsp90) members. Among these, one, glucose-regulated protein 94 (PfGrp94), is localized in the endoplasmic reticulum (ER). Both the cytosolic and ER-based Hsp90s are essential for parasite survival under all growth conditions. The cytosolic version has been extensively studied and has been targeted in several efforts through the repurposing of anticancer therapeutics as antimalarial drugs. However, PfGrp94 has not been fully characterized and some of its functions related to the ER stress response are not fully understood. Structural analysis of the recombinant full-length PfGrp94 protein showed a predominantly α-helical secondary structure and its thermal resilience was modulated by 5'-N-ethyl-carboxamide-adenosine (NECA) and nucleotides ATP/ADP. PfGrp94 exhibits ATPase activity and suppressed heat-induced aggregation of a model substrate, malate dehydrogenase, in a nucleotide-dependent manner. However, these PfGrp94 chaperone functions were abrogated by NECA. Molecular docking and molecular dynamics (MD) simulations showed that NECA interacted with unique residues on PfGrp94, which could be potentially exploited for selective drug design. Finally, using parasites maintained at the red blood stage, NECA exhibited moderate antiplasmodial activity (IC50 of 4.3, 7.4, and 10.0 μM) against three different P. falciparum strains. Findings from this study provide the first direct evidence for the correlation between in silico, biochemical, and invitro data toward utilizing the ER-based chaperone, PfGrp94, as a drug target against the malaria parasites.

A lupeol derivative and other isolates with antiplasmodial activity from the stem root of Rauvolfia mannii Stapf. (Apocynaceae)

Rauvolfia mannii is a plant from western and eastern areas of African continent and is widely used in folk medicine for the treatment of various diseases including malaria. Herein, one previously undescribed acylated triterpene (1), together with five already published natural products (2-6) were removed from its roots. The chemical structures of these compounds were determined by spectroscopic and spectrometric means (NMR, HRESIMS, IR and UV). In addition to the isolated triterpenoids, components 5 and 6 are also newly reported from the genus Rauvolfia. Moreover, some constituents were further tested against the chloroquine-sensitive strain of P. falciparum (3D7). It has been found that 3 and 4 showed a moderate antiplasmodial activity with IC50 values of 46.25 and 39.79 µM respectively.

Isoliquiritigenin from licorice root: A multi-stage anti-malarial with synergistic impact on multidrug-resistant P. falciparum

IntroductionMalaria control is hindered by drug-resistant parasites, leading to a shortage of effective drugs. There is a need to find new, better antimalarial drug. Traditional Chinese Medicine (TCM) are more accessible and cheaper alternative for combating resistance in the treatment of malaria, therefore the anti-malarial efficacy of root extracts and isolated phytomolecules from Glycyrrhiza glabra L was assessed. MethodsThe anti-plasmodial potential of root extracts and isolated phytomolecules from Glycyrrhiza glabra L. was assessed using the Giemsa staining method. In- vivo, antimalarial efficacy was evaluated by conducting a four-day suppression test in a mouse model. The mechanistic studies of ISL were carried out using caspase-like activity, mitochondrial membrane potential, and reactive oxygen species (ROS) assay. Further, proteomics analysis was carried out by LC-MS/MS. The interaction of the combinations was evaluated using the fixed ratio method by calculating the fractional inhibitory concentration (FIC). ResultsExtracts of G. glabra contain Phytomolecule(s) with moderate anti-plasmodial activity against multidrug-resistant strain (K1) of P. falciparum. Isoliquiritigenin (ISL) exhibited a significant reduction in parasitemia, resulting in an enhancement of the mean survival time in Plasmodium yoelii nigeriensis infected mice. ISL showed potent activity with no cytotoxic effect and increased caspase-3 activity, leading increasing reactive oxygen species (ROS) and loss of mitochondrial potential. ISL also displayed synergy with chloroquine, glabridin and liquiritigenin against multi-drug-resistant P. falciparum. DiscussionThe present study found ISL to be a potential phytomolecule of G. glabra. The study explored the mechanism of action of ISL and suggested its suitability for further study in managing drug-resistant malaria.

Bioguided antiplasmodial isolation of six new labdane-type diterpenoids from the stem bark of Croton sylvaticus Hochst. Ex. Krauss

The CH2Cl2-MeOH (1:1, v/v) extract of Croton sylvaticus stem bark selectively exhibited good antiplasmodial activity during preliminary screening against the multidrug-resistant (Dd2) and chloroquine sensitive (3D7) strains of Plasmodium falciparum with IC50 values of 10.57 and 18.47 μg/mL, respectively. After fractionation, the fractions exhibited moderate to good activity with IC50 values ranging from 4.31 to 25.49 μg/mL. The purification of these fractions led to the isolation of six new labdane-type diterpenoids named sylvacrotonins AF (16), alongside seven known compounds (713). Their structures were determined based on the analysis of their NMR and MS data. The isolated compounds were assessed in vitro for their antiplasmodial activity against Pf3D7 and PfDd2. The new labdane-type diterpenoids showed moderate antiplasmodial activity against the two P. falciparum strains, with compound 6 being the most active, with IC50 values of 11.26 and 21.80 μg/mL against PfDd2 and Pf3D7, respectively. Cytotoxic assays were performed on African green monkey kidney Vero cells to ensure that the obtained activity was specific to the parasites. Interestingly, all the tested extracts, fractions, and isolated compounds showed acceptable selectivity (SI > 10) against both Plasmodium strains, except fractions CSB-E (SI = 3.93) and CSB-C (SI = 9.22) against Pf3D7. Globally, with resistance indexes (RIs) lower than 1, all the tested samples were found to be more active against multidrug-resistant (PfDd2) than sensitive (Pf3D7) strains. Furthermore, all the isolated compounds exhibited cell cytotoxicity in the normal Vero cell line. The results from this study confirm the use of C. sylvaticus in malaria-endemic countries for its management and suggest that further lead-optimization studies on hit compounds could drive to the identification of potential lead molecules for antimalarial control and eradication.

New antiplasmodial piperazine alkaloid derivatives from Rauvolfia mannii Stapf. (Apocynaceae)

The stem bark extract of Rauvolfia mannii (Apocynaceae) was submitted to chemical and antiparasitic investigations. Chemical analyses resulted in the isolation of two new furyl-piperazine alkaloid derivatives namely 2-(2″-hydroxymethylhexyloxy)furan-5′-yl)-6-(piperazin-7-yl)piperazine (1) and 2-(2″-methylhexyloxy)furan-5′-yl)-6-(piperazin-7-yl)piperazine (2), along with six known compounds. The structures (including the relative stereochemistry) of these secondary metabolites were determined based on spectroscopic data, chemical correlations and comparison with the literature data. 1 and 2 display at least one piperazine ring, hence induce Rauvolfia alkaloids bearing rare skeletons. They are in fact, reported for the first time from the Apocynaceae family. Additionally, two of the isolates, arjunolic acid (5) and echitamine (7) showed moderate antiplasmodial activity against the chloroquine resistant (CQR) Plasmodium falciparum Dd2 with IC50 values of 22.5 and 16.3 μg/mL respectively.

Antiplasmodial and interferon-gamma-modulating activities of the aqueous extract of stone breaker (Phyllanthus niruri Linn.) in malaria infection.

Plasmodium falciparum parasites are the primary cause of malaria across Africa. The problem of drug resistance to malaria is ever growing and novel therapeutic strategies need to be developed, particularly those targeting the parasite and also the host or host-pathogen interaction. Previous studies have shown that the development of cerebral malaria (CM) is related to dysregulation of the immune system in a murine malaria model of experimental cerebral malaria. It involves a complex interaction of events and interferon-gamma seems to be the unifying factor. Therefore, the antiplasmodial activity targeting the parasite and immunomodulatory strategies that reduce overall host inflammation, with IFN-γ in focus, could delay CM onset and prove beneficial in malaria infection therapy. Phyllanthus niruri is used to treat fever and other symptoms of malaria in Nigeria. Its modes of action as an anti-malarial remedy have not been exhaustively investigated. This study therefore examined the aqueous extract of P. niruri (PE) for its antiplasmodial activity in vitro using the Plasmodium falciparum HB3 strain. Furthermore, in vivo murine malaria model using the Plasmodium berghei ANKA strain was used to investigate its anti-malarial effects. We showed that PE has multiple anti-malarial effects, including anti-parasitic and host immunomodulatory activities. Co-culture of P. falciparum with PE and some of its phytoconstituents drastically reduced parasite number. PE also decreased parasitemia, and increased the survival of infected mice. We also observed that the integrity of the blood-brain barrier was maintained in the PE-treated mice. The results confirmed that PE showed moderate antiplasmodial activity. In vivo murine malaria model using P. berghei ANKA for experimental cerebral malaria revealed that PE suppressed parasite growth, and modulate the production of interferon-gamma. The findings demonstrate that PE affects malaria progression, targeting parasites and host cells.

Phytochemical screening, antioxidant analyses, and in vitro and in vivo antimalarial activities of herbal medicinal plant - Rotheca serrata (L.) Steane & Mabb.

Ethnopharmacological relevanceMalaria is a major global health concern that is presently challenged by the emergence of Plasmodium falciparum (Pf) resistance to mainstay artemisinin-based combination therapies (ACTs). Hence, the discovery of novel and effective antimalarial drugs is pivotal to treating and controlling malaria. For many years, traditional plant-based herbal medicines have been employed in the treatment of various illnesses. Rotheca serrata (L.) Steane & Mabb. belongs to the Lamiaceae family that has been traditionally used to treat, cure, and prevent numerous diseases including malaria. AimThe present investigation sought to assess the phytoconstituents, antioxidant, cytotoxicity, antimalarial activities of Rotheca serrata extract and its fractions. The in vitro antiplasmodial activity was assessed in chloroquine-sensitive Pf3D7 and artemisinin-resistant PfCam3.IR539T cultures, and the in vivo antimalarial activity was analyzed in Plasmodium berghei (Pb) ANKA strain-infected BALB/c mouse model. Materials and methodsThe fresh leaves of Rotheca serrata were extracted in methanol (RsMeOH crude leaf extract). A portion of the extract was used to prepare successive solvent fractions using ethyl acetate (RsEA) and hexane (RsHex). The in vitro antiplasmodial activity was evaluated using [3H]-hypoxanthine incorporation assays against Pf3D7 and PfCam3.IR539T cultures. In vitro cytotoxicity study on HeLa, HEK-293T, and MCF-7 cell lines was carried out using MTT assay. The human red blood cells (RBCs) were used to perform the hemolysis assays. In vitro antioxidant studies and detailed phytochemical analysis were performed using GC-MS and FTIR. The four-day Rane's test was performed to evaluate the in vivo antimalarial activity against Pb ANKA strain-infected mice. ResultsPhytochemical quantification of Rotheca serrata extract (RsMeOH) and its fractions (RsEA and RsHex) revealed that RsMeOH crude extract and RsEA fraction had higher contents of total phenol and flavonoid than RsHex fraction. The RsEA fraction showed potent in vitro antiplasmodial activity against Pf3D7 and PfCam3.IR539T with IC50 values of 9.24 ± 0.52 μg/mL and 17.41 ± 0.43 μg/mL, respectively. The RsMeOH crude extract exhibited moderate antiplasmodial activity while the RsHex fraction showed the least antiplasmodial activity. The GC-MS and FTIR analysis of RsMeOH and RsEA revealed the presence of triterpenes, phenols, and hydrocarbons as major constituents. The RsMeOH crude extract was non-hemolytic and non-cytotoxic to HeLa, HEK-293T, and MCF-7 cell lines. The in vivo studies showed that a 1200 mg/kg dose of RsMeOH crude extract could significantly suppress parasitemia by ∼63% and prolong the survival of treated mice by ∼10 days. The in vivo antiplasmodial activity of RsMeOH was better than the RsEA fraction. ConclusionThe findings of this study demonstrated that traditionally used herbal medicinal plants like R. serrata provide a platform for the identification and isolation of potent bioactive phytochemicals that in turn can promote the antimalarial drug research. RsMeOH crude extract and RsEA fraction showed antiplasmodial, antimalarial and antioxidant activities. Chemical fingerprinting analysis suggested the presence of bioactive phytocompounds that are known for their antimalarial effects. Further detailed investigations on RsMeOH crude extract and RsEA fraction would be needed for the identification of the entire repertoire of the active antimalarial components with potent pharmaceutical and therapeutic values.

Evaluating phytochemical constituents and in-vitro antiplasmodial and antioxidant activities of Fadogiella stigmatoloba, Hygrophylla auriculata, Hylodesmum repandum, and Porphyrostemma chevalieri extracts

IntroductionFadogiella stigmatoloba, Hygrophylla auriculata, Hylodesmum repandum and Porphyrostemma chevalieri are used against malaria in traditional medicine in the Democratic Republic of the Congo (DRC). To evaluate their potential in the treatment of this disease, the in vitro antiplasmodial property of these four plants was evaluated. All experiments were conducted on methanolic extracts performed on selected organ parts of these plants. MethodsThe methanolic extracts, obtained by maceration, were firstly screened in vitro against the chloroquine sensitive (3D7) and resistant (W2) Plasmodium falciparum strains by the measurement of lactate dehydrogenase activity, and on human keratinocytes (HaCat) cells by the MTT assay to determine their selectivity indices (SI). Secondly, the antioxidant activity of the same extracts was evaluated using DPPH and FRAP assays. Finally, the presence of specific phytochemical constituents was evaluated using standard methods and tentatively identified by GC-MS. ResultsAn optimum antiplasmodial activity (IC50 = 3.4 ± 0.7 μg/mL, for 3D7, SI = 58.2; IC50 = 7 ± 1.0 μg/mL, for W2, SI = 28.3) was obtained with the leave extract of P. chevalieri. The leaves (for F. stigmatoloba and H. repandum), and the aerial part (for H. repandum) extracts showed promising and moderate antiplasmodial activities against respectively the 3D7 strain (IC50: <15 μg/mL), and W2 strain (IC50:15–50 μg/mL). All extracts presented a weak cytotoxic effect (IC50: >100 μg/mL) on HaCat cells. For the antioxidant test, the most interesting activity was obtained with the leaf extract of P. chevalieri. The GC–MS analysis of these four plants species extracts revealed the presence of various compounds, such as Ethyl 2-nonenoate, 2-(2-Hydroxy-2-phenylethyl)-3,5,6-trimethyl pyrazine, Palmitic Acid, Ethyl palmitate, Ethyl linolenate, and N-Acetyltyramine. ConclusionBased on the obtained results, P. chevalieri could be selected for further investigations or ⁄and for the management of malaria after standardization.

Toxicity Studies and in vivo Antiplasmodial Evaluation of Leaf and Stem Bark Extracts of Terminalia avicennioides

Malaria is one of the most serious infectious diseases found in the tropics and subtropics. P. falcifarum resistance to almost all anti-malarial drugs has necessitated the search for anti-malarial compounds. The aim of this study is to investigate the antiplasmodial effects of crude leaf and stem bark extracts of T. avicennioides, a plant utilized by traditional healers in Northern Nigeria to treat malaria and other ailments. Brine shrimp lethality (cytotoxicity) assay and acute toxicity were also evaluated, which are considered a useful tool for preliminary assessment of toxicity in plant extracts. The median lethal dosage (LD50) was calculated by administering different doses of the extract (100–4000 mg/kg) intraperitoneally to three groups of three mice each for 24 hours and observing the animals for physical sign of toxicity. Three models were employed to assess the extracts antiplasmodial effectiveness in vivo against the rodent malaria parasite Plasmodium berghei: suppressive, curative, and repository. The leaf and stem bark extracts were found to show significant toxicity to brine shrimp larvae of Artemia salina in the brine shrimp lethality test with LC50 values of &gt;1000 and 29.6 respectively. Excitation, paw licking, and death were symptoms of acute toxicity of the extracts based on physical and behavioral observations. Death was recorded at 1000 mg/Kg of the stem bark extract and the LD50 is ≤100 mg/Kg body weight while for the leaf extract it was estimated to be ≤600 mg/Kg with no death record. In vivo evaluation revealed that the extracts significantly (P &lt;0.05) reduced parasite count in all models (suppressive, curative and prophylactic), with high average percentage inhibition of parasitaemia (54.68, 58.67 and 65.61%) seen in both T. avicennioides leaf and stem bark extracts, which was comparable to that produced by chloroquine and artesunate, respectively (64.31&amp;93.1; 70.08&amp;80.67; 63.40&amp;75.20%). Both extracts had moderate antiplasmodial activity and were non-toxic to mice and brine shrimps. This finding validates the plant's traditional use in malaria treatment.

Polyketide- and Terpenoid-Derived Metabolites Produced by a Marine-Derived Fungus, Peroneutypa sp.

Bioassay-guided investigation of the EtOAc-soluble extract of a culture of the marine-derived fungus Peroneutypa sp. M16 led to the isolation of seven new polyketide- and terpenoid-derived metabolites (1, 2, 4-8), along with known polyketides (3, 9-13). Structures of compounds 1, 2, and 4-8 were established by analysis of spectroscopic data. Absolute configurations of compounds 1, 2, 4, 6, 7, and 8 were determined by the comparison of experimental ECD spectra with calculated CD data. Compound 5 exhibited moderate antiplasmodial activity against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum.

Harmicens, Novel Harmine and Ferrocene Hybrids: Design, Synthesis and Biological Activity.

Cancer and malaria are both global health threats. Due to the increase in the resistance to the known drugs, research on new active substances is a priority. Here, we present the design, synthesis, and evaluation of the biological activity of harmicens, hybrids composed of covalently bound harmine/β-carboline and ferrocene scaffolds. Structural diversity was achieved by varying the type and length of the linker between the β-carboline ring and ferrocene, as well as its position on the β-carboline ring. Triazole-type harmicens were prepared using Cu(I)-catalyzed azide-alkyne cycloaddition, while the synthesis of amide-type harmicens was carried out by applying a standard coupling reaction. The results of in vitro biological assays showed that the harmicens exerted moderate antiplasmodial activity against the erythrocytic stage of P. falciparum (IC50 in submicromolar and low micromolar range) and significant and selective antiproliferative activity against the MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range, SI > 5.9). Cell localization experiments showed different localizations of nonselective harmicene 36 and HCT116-selective compound 28, which clearly entered the nucleus. A cell cycle analysis revealed that selective harmicene 28 had already induced G1 cell cycle arrest after 24 h, followed by G2/M arrest with a concomitant drastic reduction in the percentage of cells in the S phase, whereas the effect of nonselective compound 36 on the cell cycle was much less pronounced, which agreed with their different localizations within the cell.

Antiplasmodial and antimycobacterial activities of crude and lead-like enhanced extracts from Namibian medicinal plants

Ethnopharmacological relevanceEight indigenous medicinal plants which are used traditionally for the treatment of tuberculosis (TB), malaria, and associated symptoms, were selected for this study. Aim of studyThe aim of this study was to evaluate the antiplasmodial and antimycobacterial activities of the organic and aqueous crude extracts of different plant parts, by comparing the activities of subfractions (lead-like enhanced [LLE] extracts and methanol fractions) prepared from the bioactive crude extracts. Materials & methodsCrude aqueous and organic extracts were prepared for 25 different plant parts obtained from eight plant species. In vitro antiplasmodial activity was evaluated using the parasite lactate dehydrogenase assay against chloroquine-sensitive Plasmodium falciparum NF54 and in vitro antimycobacterial activity determined against the Mycobacterium tuberculosis H37Rv-GFP strain in a standard broth microdilution assay. The bioactive crude extracts were subjected to solid phase extraction with Strata-X 33 μm reversed phase cartridges and eluted with 70:30 MeOH: H2O:1% trifluoroacetic acid to yield the LLE extract, followed by a methanol rinse, herein referred to as the MeOH fraction. Both fractions were evaluated for antiplasmodial and antimycobacterial activity. Proton nuclear magnetic resonance spectroscopy (1H-NMR) and ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) profiling of the crude and active fractions of the phytochemically unexplored Sarcocaulon marlothii Engl. were performed to aid the identification of a potential antiplasmodial lead compound. ResultsTen of the aqueous and organic crude extracts displayed antimycobacterial activity, with minimum inhibitory concentration (MIC90) values ranging from 9.9 to 86.8 μg/mL, and four crude extracts showed antiplasmodial activity with inhibitory concentration (IC50) values between 5.2 and 17.8 μg/mL. Although the stems of S. marlothii are traditionally used to treat TB and related symptoms, the two crude extracts displayed weak antimycobacterial activity (MIC90 > 100 μg/mL) while the crude organic extract displayed moderate antiplasmodial activity with an IC50 value of 8.8 μg/mL. None of the LLE extracts prepared from the ten antimycobacterial-active crudes displayed any significant activity (MIC90 > 125 μg/mL). In contrast, fractionation of three antiplasmodial-active, crude organic extracts yielded MeOH fractions which displayed a 2-fold to 19-fold increase in activity. The 1H-NMR profiles of the active MeOH fraction (IC50 4.3 μg/mL) of S. marlothii (organic, stem) revealed the likely presence of an unidentified trisubstituted cinnamic acid derivative as one of the major compounds and UPLC-MS/MS data provided additional evidence that the compound may be a hydroxycinnamic acid derivative. Unfortunately, owing to the paucity of the material obtained, we were unable to purify and unequivocally determine the structure of this active compound. ConclusionsThis is the first report on the phytochemical profiling of S. marlothii and, based on the antiplasmodial activity recorded, it merits an in-depth phytochemical analysis for the unequivocal characterization of a potential antiplasmodial lead compound. Results from this study lend support to the effectiveness of extract enrichment in combination with NMR fingerprinting for antiplasmodial lead identification.

Antiplasmodial Activity of Vachellia xanthophloea (Benth.) P.J.H. Hurter (African Fever Tree) and Its Constituents.

Vachellia xanthophloea is used in Zulu traditional medicine as an antimalarial remedy. A moderate antiplasmodial activity was previously reported for extracts of the plant against D10 Plasmodium falciparum. This study aimed to identify the phytochemicals responsible for the antiplasmodial activity of the leaf extract. The compounds were isolated by chromatography and their structures were determined using spectroscopic and spectrometric methods. The antiplasmodial activity was evaluated using a parasite lactate dehydrogenase assay and cytotoxicity was determined using a resazurin assay. The ethyl acetate fraction inhibited P. falciparum with IC50 = 10.6 µg/mL and showed minimal cytotoxicity (98% cell viability at 33 µg/mL). The chromatographic purification of this fraction afforded sixteen compounds, including two new flavonoids. A 1:1 mixture of phytol and lupeol was also isolated from the hexane fraction. All the compounds were reported from V. xanthophloea for the first time. Among the isolated metabolites, methyl gallate displayed the best activity against P. falciparum (IC50 = 1.2 µg/mL), with a 68% viability of HeLa cells at 10 µg/mL. Therefore, methyl gallate was responsible for the antiplasmodial activity of the V. xanthophloea leaf extract and its presence in the leaf extract might account for the folkloric use of the plant as an antimalarial remedy.

Antiplasmodial activity of alkaloids from Croton linearis leaves

Croton linearis is a shrub that grows in Caribbean regions, which is rich in metabolites such as alkaloids. The main aim of this study was to evaluate the antiplasmodial effect of alkaloids from this species. Three isoquinoline alkaloids, i.e. reticuline (1), laudanidine (2) and 8,14-dihydrosalutaridine (3), were isolated from the leaves of C. linearis by flash chromatography and semi-preparative HPLC-DAD-MS. Their structures were elucidated by spectroscopic techniques. Antiplasmodial activity against the chloroquine-resistant strain Plasmodium falciparum K1 and cytotoxicity against MRC-5 cells (human fetal lung fibroblast cells) were assessed in vitro. Reticuline, laudanidine and 8,14-dihydrosalutaridine showed moderate antiplasmodial activity with IC50 values of 46.8 ± 0.6, 17.7 ± 0.6 and 16.0 ± 0.5 μM, respectively, but no cytotoxicity was observed in a concentration up to 64.0 μM. This is the first report on the antiplasmodial activity of laudanidine and 8,14-dihydrosalutaridine.

Anti-plasmodial, Cytotoxic and Antioxidant Activities of Selected Ghanaian Medicinal Plants.

Malaria affects about half of the world's population. The sub-Saharan African region is the most affected. Plant natural products have been a major source of antimalarial drugs; the first (quinine) and present (artemisinin) antimalarials are of natural product origin. Some secondary metabolites demonstrate adjuvant antioxidant effects and selective activity. The focus of this study was to investigate the anti-plasmodial activity, cytotoxicities and antioxidant properties of eight (8) Ghanaian medicinal plants. The anti-plasmodial activity was determined using the SYBR green assay and the tetrazolium-based colorimetric assay (MTT) was employed to assess cytotoxicity of extracts to human RBCs and HL-60 cells. Antioxidant potential of plant extracts was evaluated using Folin-Ciocalteu and superoxide dismutase assays. Phytochemical contstituents of the plant extracts were also assessed. All the extracts demonstrated anti-plasmodial activities at concentrations <50 μg/ml. Parkia clappertoniana and Terminalia ivorensis elicited the strongest anti-plasmodial activities with 50% inhibitory concentrations (IC50) of 1.13 μg/ml and 0.95 μg/ml, respectively. This is the first report on anti-plasmodial activities of Baphia nitida, Tabernaemontana crassa and Treculia Africana. T. Africana showed moderate anti-plasmodial activity with IC50 value of 6.62 µg/mL. Extracts of P. clappertoniana, T. Africana and T. ivorensis (0.4 mg/mL) showed >50% antioxidant effect (SOD). The extracts were not cytotoxicity towards RBCs at the concentration tested (200 μg/ml) but were weakly cytotoxic to HL-60 cell. Selectivity indices of most of the extracts were greater than 10. Our results suggest that most of the plant extracts have strong anti-plasmodial activity and antioxidant activity which warrants further investigations.

Antiplasmodial and cytotoxic effects of the methanol extract, canthinone alkaloids, squalene- and protolimonoid-type triterpenes from Homalolepis suffruticosa roots

Ethnopharmacological relevanceDifferent species of the Simaroubaceae family are used in traditional medicine to treat malaria. Among these is Homalolepis suffruticosa (syn. Simaba suffruticosa and Quassia suffruticosa), which is native to Central Brazil and popularly known as calunga. However, there is a lack of investigation concerning its antimalarial effects. Aim of the studyTo investigate the antiplasmodial and cytotoxic effects of the isolated metabolites and methanol extract from H. suffruticosa roots as well as to conduct the dereplication of this extract aiming to characterize its metabolic profile by UPLC-DAD-ESI-MS/MS. Materials and methodsMethanol extract of the H. suffruticosa roots and six isolated compounds were evaluated against chloroquine-resistant Plasmodium falciparum W2 strain by the PfLDH method and cytotoxicity in HepG2 cells by the MTT assay. Dereplication of the extract was performed by UPLC-DAD-ESI-MS/MS. ResultsThe six isolated compounds disclosed high to moderate antiplasmodial activity (IC50 0.0548 ± 0.0083 μg/mL to 26.65 ± 2.40 μg/mL) and cytotoxicity was in the range of CC50 0.62 ± 0.33 μg/mL to 56.43 ± 2.54 μg/mL, while 5-metoxycantin-6-one proved to be the most potent constituent of the six assayed ones. The methanol extract of the roots showed high in vitro antiplasmodial activity (IC50 1.88 ± 0.56 μg/mL), moderate cytotoxicity (CC50 41.93 ± 2.30 μg/mL), and good selectivity index (SI = 22.30). Finally, C20 quassinoids and canthin-6-one alkaloids were putatively identified in the H. suffruticosa methanol extract by LC-MS. ConclusionsTaken together, the isolated compounds, mainly the 5-metoxycantin-6-one and the methanol extract from H. suffruticosa roots, disclose good antiplasmodial activity, supporting the ethnopharmacological history of the Simaroubaceae species as traditional antimalarial drugs.

X-ray Structure Determination, Antioxidant Voltammetry Studies of Butein and 2',4'-Dihydroxy-3,4-dimethoxychalcone. Computational Studies of 4 Structurally Related 2',4'-diOH Chalcones to Examine Their Antimalarial Activity by Binding to Falcipain-2.

Malaria is a huge global health burden with resistance to currently available medicines resulting in the search for newer antimalarial compounds from traditional medicinal plants in malaria-endemic regions. Previous studies on two chalcones, homobutein and 5-prenylbutein, present in E. abyssinica, have shown moderate antiplasmodial activity. Here, we describe results from experimental and computational investigations of four structurally related chalcones, butein, 2′,4′-dihydroxy-3,4-dimethoxychalcone (DHDM), homobutein and 5-prenylbutein to elucidate possible molecular mechanisms by which these compounds clear malaria parasites. The crystal structures of butein and DHDM show that butein engages in more hydrogen bonding and consequently, more intermolecular interactions than DHDM. Rotating ring-disk electrode (RRDE) voltammetry results show that butein has a higher antioxidant activity towards the superoxide radical anion compared to DHDM. Computational docking experiments were conducted to examine the inhibitory potential of all four compounds on falcipain-2, a cysteine protease that is involved in the degradation of hemoglobin in plasmodium-infected red blood cells of the host. Overall, this work suggests butein as a better antimalarial compound due to its structural features which allow it to have greater intermolecular interactions, higher antioxidant activity and to create a covalent complex at the active site of falcipain-2.