In vitro and in vivo antiplasmodial activity of three Rwandan medicinal plants and identification of their active compounds.

PubMed

Muganga, Raymond; Angenot, Luc; Tits, Monique; Frédérich, Michel

2014-04-01

In our previous study, we reported the interesting in vitro antiplasmodial activity of some Rwandan plant extracts. This gave rise to the need for these extracts to also be evaluated in vivo and to identify the compounds responsible for their antiplasmodial activity. The aim of our study was, on the one hand, to evaluate the antiplasmodial activity in vivo and the safety of the selected Rwandan medicinal plants used in the treatment of malaria, with the objective of promoting the development of improved traditional medicines and, on the other hand, to identify the active ingredients in the plants. Plant extracts were selected according to their selectivity index. The in vivo antiplasmodial activity of aqueous, methanolic, and dichloromethane extracts was then evaluated using the classical 4-day suppressive test on Plasmodium berghei infected mice. The activity of the plant extracts was estimated by measuring the percentage of parasitemia reduction, and the survival of the experimental animals was recorded. A bioguided fractionation was performed for the most promising plants, in terms of antiplasmodial activity, in order to isolate active compounds identified by means of spectroscopic and spectrometric methods. The highest level of antiplasmodial activity was observed with the methanolic extract of Fuerstia africana (> 70 %) on days 4 and 7 post-treatment after intraperitoneal injection and on day 7 using oral administration. After oral administration, the level of parasitemia reduction observed on day 4 post-infection was 44 % and 37 % with the aqueous extract of Terminalia mollis and Zanthoxylum chalybeum, respectively. However, the Z. chalybeum extract presented a high level of toxicity after intraperitoneal injection, with no animals surviving on day 1 post-treatment. F. africana, on the other hand, was safer with 40 % mouse survival on day 20 post-treatment. Ferruginol is already known as the active ingredient in F. Africana, and ellagic acid (IC50 = 175 ng/mL) and nitidine (IC50 = 77.5 ng/mL) were identified as the main active constituents of T. mollis and Z. chalybeum, respectively. F. africana presented very promising antiplasmodial activity in vivo. Although most of the plants tested showed some level of antiplasmodial activity, some of these plants may be toxic. This study revealed for the first time the role of ellagic acid and nitidine as the main antimalarial compounds in T. mollis and Z. chalybeum, respectively. Georg Thieme Verlag KG Stuttgart · New York.

Chemical composition, cytotoxicity and in vitro antitrypanosomal and antiplasmodial activity of the essential oils of four Cymbopogon species from Benin.

PubMed

Kpoviessi, Salomé; Bero, Joanne; Agbani, Pierre; Gbaguidi, Fernand; Kpadonou-Kpoviessi, Bénédicta; Sinsin, Brice; Accrombessi, Georges; Frédérich, Michel; Moudachirou, Mansourou; Quetin-Leclercq, Joëlle

2014-01-01

Cymbopogon species are largely used in folk medicine for the treatment of many diseases some of which related to parasitical diseases as fevers and headaches. As part of our research on antiparasitic essential oils from Beninese plants, we decided to evaluate the in vitro antiplasmodial and antitrypanosomal activities of essential oils of four Cymbopogon species used in traditional medicine as well as their cytotoxicity. The essential oils of four Cymbopogon species Cymbopogon citratus (I), Cymbopogon giganteus (II), Cymbopogon nardus (III) and Cymbopogon schoenantus (IV) from Benin obtained by hydrodistillation were analysed by GC/MS and GC/FID and were tested in vitro against Trypanosoma brucei brucei and Plasmodium falciparum respectively for antitrypanosomal and antiplasmodial activities. Cytotoxicity was evaluated in vitro against Chinese Hamster Ovary (CHO) cells and the human non cancer fibroblast cell line (WI38) through MTT assay to evaluate the selectivity. All tested oils showed a strong antitrypanosomal activity with a good selectivity. Sample II was the most active against Trypanosoma brucei brucei and could be considered as a good candidate. It was less active against Plasmodium falciparum. Samples II, III and IV had low or no cytotoxicity, but the essential oil of Cymbopogon citratus (I), was toxic against CHO cells and moderately toxic against WI38 cells and needs further toxicological studies. Sample I (29 compounds) was characterised by the presence as main constituents of geranial, neral, β-pinene and cis-geraniol; sample II (53 compounds) by trans-p-mentha-1(7),8-dien-2-ol, trans-carveol, trans-p-mentha-2,8-dienol, cis-p-mentha-2,8-dienol, cis-p-mentha-1(7),8-dien-2-ol, limonene, cis-carveol and cis-carvone; sample III (28 compounds) by β-citronellal, nerol, β-citronellol, elemol and limonene and sample IV (41 compounds) by piperitone, (+)-2-carene, limonene, elemol and β-eudesmol. Our study shows that essential oils of Cymbopogon genus can be a good source of antitrypanosomal agents. This is the first report on the activity of these essential oils against Trypanosoma brucei brucei, Plasmodium falciparum and analysis of their cytotoxicity. © 2013 Published by Elsevier Ireland Ltd.

Synthesis and biological evaluation of a series of non-hemiacetal ester derivatives of artemisinin.

PubMed

Zuma, Nonkululeko H; Smit, Frans J; de Kock, Carmen; Combrinck, Jill; Smith, Peter J; N'Da, David D

2016-10-21

In an attempt to improve the efficacy and stability of current, clinically used artemisinins, a series non-hemiacetal ester derivatives of artemisinin were synthesized and evaluated for their in vitro antiplasmodial and anticancer activities as well as cytotoxicities. These esters were synthesized through the reaction of acid anhydrides, or acid chlorides with artemisinin derived alcohol. In vitro antiplasmodial activity assessments were conducted against intraerythrocytic NF54 and Dd2 Plasmodium falciparum strains. Cytotoxicities were assessed, using normal human fetal lung fibroblast (WI-38) and Chinese hamster ovarian (CHO) mammalian cell lines, while anticancer activities were tested by using panels with three cell lines, consisting of renal (TK10), melanoma (UACC62) and breast (MCF7) cancer cells. Most compounds were found active against the breast cancer cell line. Since antiplasmodial activities for most compounds were found comparable only to that of artesunate, this study did not yield any esters with significantly improved antimalarial efficacies, nor did it deliver any promising antitumor hits. However, from the outcomes of this study, compounds with good safety profiles and increased thermal stabilities, compared to the clinically used artemisinins, were identified. The benzoate derivative 11 was found to have antimalarial activity, comparable to that of dihydroartemisinin and was it subsequently identified as a candidate for further investigation in the urgent search for new, safe and effective antimalarial drugs. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Evaluation of substituted phenalenone analogues as antiplasmodial agents.

PubMed

Gutiérrez, David; Flores, Ninoska; Abad-Grillo, Teresa; McNaughton-Smith, Grant

2013-10-01

A set of derivatives encompassing structural modifications on the privileged phenalenone scaffold were assessed for their antiplasmodial activities against a strain of chloroquine sensitive Plasmodium falciparum F32. Two compounds exhibited considerable effects against the malaria parasite (IC₅₀ ≤ 1 μg/mL), one of which maintained the same level of activity in a chloroquine-resistant strain. This is the first record of antiplasmodial activity on this type of scaffold, providing a new structural motif as a new lead for antimalarial activity. Copyright © 2013 Elsevier Inc. All rights reserved.

Synthesis of silver nanoparticles using leaves of Catharanthus roseus Linn. G. Don and their antiplasmodial activities

PubMed Central

Ponarulselvam, S; Panneerselvam, C; Murugan, K; Aarthi, N; Kalimuthu, K; Thangamani, S

2012-01-01

Objective To develop a novel approach for the green synthesis of silver nanoparticles using aqueous leaves extracts of Catharanthus roseus (C. roseus) Linn. G. Don which has been proven active against malaria parasite Plasmodium falciparum (P. falciparum). Methods Characterizations were determined by using ultraviolet-visible (UV-Vis) spectrophotometry, scanning electron microscopy (SEM), energy dispersive X-ray and X-ray diffraction. Results SEM showed the formation of silver nanoparticles with an average size of 35–55 nm. X-ray diffraction analysis showed that the particles were crystalline in nature with face centred cubic structure of the bulk silver with the broad peaks at 32.4, 46.4 and 28.0. Conclusions It can be concluded that the leaves of C. roseus can be good source for synthesis of silver nanoparticle which shows antiplasmodial activity against P. falciparum. The important outcome of the study will be the development of value added products from medicinal plants C. roseus for biomedical and nanotechnology based industries. PMID:23569974

The antiplasmodial agents of the stem bark of Entandrophragma angolense (Meliaceae).

PubMed

Bickii, Jean; Tchouya, Guy Raymond Feuya; Tchouankeu, Jean Claude; Tsamo, Etienne

2006-11-13

In the search of active principles from the stem bark of Entandrophragma angolense, we submitted the compounds isolated from the dichloromethane-methanol (1:1) extract of the stem bark to antimalarial test against chloroquine resistant strain W2 of Plasmodium falciparum malaria parasite. Only 7alpha-obacunyl acetate and a cycloartane derivative exhibited a good activity, with IC(50)s of 2 and 5.4 microg/ml respectively. Other compounds were moderately active.

In vitro antiplasmodial and cytotoxic properties of some medicinal plants from western Burkina Faso.

PubMed

Sanon, Souleymane; Gansane, Adama; Ouattara, Lamoussa P; Traore, Abdoulaye; Ouedraogo, Issa N; Tiono, Alfred; Taramelli, Donatella; Basilico, Nicoletta; Sirima, Sodiomon B

2013-01-01

Resistance of malaria parasites to existing drugs complicates treatment, but an antimalarial vaccine that could protect against this disease is not yet available. It is therefore necessary to find new effective and affordable medicines. Medicinal plants could be a potential source of antimalarial agents. Some medicinal plants from Burkina Faso were evaluated for their antiplasmodial and cytotoxic properties in vitro . Crude dichloromethane, methanol, water-methanol, aqueous and alkaloids extracts were prepared for 12 parts of 10 plants. Chloroquine-resistant malaria strain K1 was used for the in vitro sensibility assay. The Plasmodium lactacte dehydrogenase technique was used to determine the 50% inhibitory concentration of parasites activity (IC 50 ). The cytotoxic effects were determined with HepG2 cells, using the tetrazolium-based colorimetric technique, and the selectivity index (SI) was calculated. Sixty crude extracts were prepared. Seven extracts from Terminalia avicenoides showed IC 50 < 5 µg/mL. The IC 50 of dichloromethane, methanol, aqueous and alkaloids extracts ranged between 1.6 µg/mL and 4.5 µg/mL. Three crude extracts from Combretum collinum and three from Ficus capraefolia had an IC 50 ranging between 0.2 µg/mL and 2.5 µg/mL. Crude extracts from these three plants had no cytotoxic effect, with SI > 1. The other plants have mostly moderate or no antimalarial effects. Some extracts from Cordia myxa , Ficus capraefolia and Opilia celtidifolia showed cytotoxicity, with an SI ranging between 0.4 and 0.9. Our study showed a good antiplasmodial in vitro activity of Terminalia avicenoides, Combretum collinum and Ficus capraefolia . These three plants may contain antiplasmodial molecules that could be isolated by bio-guided phytochemical studies.

In vitro antiplasmodial and cytotoxic properties of some medicinal plants from western Burkina Faso

PubMed Central

Gansane, Adama; Ouattara, Lamoussa P.; Traore, Abdoulaye; Ouedraogo, Issa N.; Tiono, Alfred; Taramelli, Donatella; Basilico, Nicoletta; Sirima, Sodiomon B.

2013-01-01

Background Resistance of malaria parasites to existing drugs complicates treatment, but an antimalarial vaccine that could protect against this disease is not yet available. It is therefore necessary to find new effective and affordable medicines. Medicinal plants could be a potential source of antimalarial agents. Some medicinal plants from Burkina Faso were evaluated for their antiplasmodial and cytotoxic properties in vitro. Methods Crude dichloromethane, methanol, water-methanol, aqueous and alkaloids extracts were prepared for 12 parts of 10 plants. Chloroquine-resistant malaria strain K1 was used for the in vitro sensibility assay. The Plasmodium lactacte dehydrogenase technique was used to determine the 50% inhibitory concentration of parasites activity (IC50). The cytotoxic effects were determined with HepG2 cells, using the tetrazolium-based colorimetric technique, and the selectivity index (SI) was calculated. Results Sixty crude extracts were prepared. Seven extracts from Terminalia avicenoides showed IC50 < 5 µg/mL. The IC50 of dichloromethane, methanol, aqueous and alkaloids extracts ranged between 1.6 µg/mL and 4.5 µg/mL. Three crude extracts from Combretum collinum and three from Ficus capraefolia had an IC50 ranging between 0.2 µg/mL and 2.5 µg/mL. Crude extracts from these three plants had no cytotoxic effect, with SI > 1. The other plants have mostly moderate or no antimalarial effects. Some extracts from Cordia myxa, Ficus capraefolia and Opilia celtidifolia showed cytotoxicity, with an SI ranging between 0.4 and 0.9. Conclusion Our study showed a good antiplasmodial in vitro activity of Terminalia avicenoides, Combretum collinum and Ficus capraefolia. These three plants may contain antiplasmodial molecules that could be isolated by bio-guided phytochemical studies. PMID:29043169

Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: part 1.

PubMed

Le Manach, Claire; Gonzàlez Cabrera, Diego; Douelle, Frederic; Nchinda, Aloysius T; Younis, Yassir; Taylor, Dale; Wiesner, Lubbe; White, Karen L; Ryan, Eileen; March, Corinne; Duffy, Sandra; Avery, Vicky M; Waterson, David; Witty, Michael J; Wittlin, Sergio; Charman, Susan A; Street, Leslie J; Chibale, Kelly

2014-03-27

A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.

In vivo antiplasmodial activities of ethanolic extract and fractions of Eleucine indica.

PubMed

Ettebong, E O; Nwafor, P A; Okokon, J E

2012-09-01

To evaluate the in vivo antiplasmodial activities of the extract and fractions (n-hexane, chloroform, ethylacetate, butanol, aqueous) of the whole plant in Plasmodium berghei berghei infected mice. Oral administrations of the extract (200, 400, and 600 mg/kg) of Eleucine indica and fractions (400 mg/kg) were screened in the 4-day, repository and curative tests. Chloroquine (5 mg/kg), pyrimethamine (1.2 mg/kg) and artesunate (5 mg/kg) were used as controls. The extract showed significant (P< 0.05-0.001) dose-dependent, antiplasmodial activity in the 4-day, repository and curative tests and increased the survival times of the infected mice. All the fractions exhibited significant antiplasmodial activity with the highest being ethylacetate fraction. Eleucine indica extract and fractions possess antimalarial activity which confirms the ethnobotanical use of this plant as a malarial remedy and opens a new highway to further investigate its potentials in the on-going fight against malaria. Copyright © 2012 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

In vitro antiplasmodial activity of bacterium RJAUTHB 14 associated with marine sponge Haliclona Grant against Plasmodium falciparum.

PubMed

Jacob Inbaneson, Samuel; Ravikumar, Sundaram

2012-06-01

Malaria is the most important parasitic disease, leading to annual death of about one million people, and the Plasmodium falciparum develops resistance to well-established antimalarial drugs. The newest antiplasmodial drug from a marine microorganism helps in addressing this problem. In the present study, Haliclona Grant were collected and subjected for enumeration and isolation of associated bacteria. The count of bacterial isolates was maximum in November 2007 (18 × 10(4) colony-forming units (CFU) g(-1), and the average count was maximum during the monsoon season (117 × 10(3) CFU g(-1)). Thirty-three morphologically different bacterial isolates were isolated from Haliclona Grant, and the extracellular ethyl acetate extracts were screened for antiplasmodial activity against P. falciparum. The antiplasmodial activity of bacterium RJAUTHB 14 (11.98 μg[Symbol: see text]ml(-1)) is highly comparable with the positive control chloroquine (IC(50) 19.59 μg[Symbol: see text]ml(-1)), but the other 21 bacterial extracts showed an IC(50) value of more than 100 μg[Symbol: see text]ml(-1). Statistical analysis reveals that significant in vitro antiplasmodial activity (P < 0.05) was observed between the concentrations and time of exposure. The chemical injury to erythrocytes showed no morphological changes in erythrocytes by the ethyl acetate extract of bacterial isolates after 48 h of incubation. The in vitro antiplasmodial activity might be due to the presence of reducing sugars and alkaloids in the ethyl acetate extracts of bacterium RJAUTHB 14. The 16S rRNA gene partial sequence of bacterium RJAUTHB 14 is deposited in NCBI (GenBank accession no. GU269569). It is concluded from the present study that the ethyl acetate extracts of bacterium RJAUTHB 14 possess lead compounds for the development of antiplasmodial drugs.

HSQC-TOCSY Fingerprinting-Directed Discovery of Antiplasmodial Polyketides from the Marine Ascidian-Derived Streptomyces sp. (USC-16018).

PubMed

Buedenbender, Larissa; Robertson, Luke P; Lucantoni, Leonardo; Avery, Vicky M; Kurtböke, D İpek; Carroll, Anthony R

2018-05-30

Chemical investigations on the fermentation extract obtained from an ascidian-derived Streptomyces sp. (USC-16018) yielded a new ansamycin polyketide, herbimycin G ( 1 ), as well as a known macrocyclic polyketide, elaiophylin ( 2 ), and four known diketopiperazines ( 3 ⁻ 6 ). The structures of the compounds were elucidated based on 1D/2D NMR and MS data. The absolute configuration of 1 was established by comparison of experimental and predicted electronic circular dichroism (ECD) data. Antiplasmodial activities were tested for the natural products against chloroquine sensitive (3D7) and chloroquine resistant (Dd2) Plasmodium falciparum strains; the two polyketides ( 1 ⁻ 2 ) demonstrated an inhibition of >75% against both parasite strains and while 2 was highly cytotoxic, herbimycin G ( 1 ) showed no cytotoxicity and good predicted water solubility.

Synthesis and evaluation of the antiplasmodial activity of tryptanthrin derivatives

PubMed Central

Onambele, Liliane Abodo; Riepl, Herbert; Fischer, Rainer; Pradel, Gabriele; Prokop, Aram; Aminake, Makoah Nigel

2015-01-01

Malaria remains one of the most deadly diseases threatening humankind and is still affecting a significant proportion of the world population, especially in Africa. Chemotherapy is a vital component of the fight against the disease and new antimalarial agents are urgently needed to curb the spread of malaria parasites that are resistant to existing drugs. The natural product tryptanthrin is known for its wide range of activities, including antiplasmodial activity, but its poor solubility has undermined its development as potent antimicrobial and antiprotozoan agent. The aim of this work was to synthesize analogues of tryptanthrin and to evaluate their antiplasmodial activity against the asexual and sexual blood stages of Plasmodium falciparum. Our results suggest that most tryptanthrin analogues retained their antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant malaria parasites in the nanomolar range (30–100 nM). The antiplasmodial activity of the most active compound NT1 (IC50: 30 nM; SI: 155.9) was similar in both strains and close to that of chloroquine (IC50: 20 nM) on the sensitive strain. The antiplasmodial activity was improved with derivatization, thus pointing out the necessity to explore tryptanthrin using medicinal chemistry approaches. Ten (10) of the tested derivatives met the criteria, allowing for advancement to animal testing, i.e., SI > 100 and IC50 < 100 nM. In addition to their activity on the asexual stages, tryptanthrin and two selected derivatives (NT1 and T8) prevented the maturation of gametocytes at their IC90 concentrations, indicating a transmission-blocking potential. Moreover, NT1 was able to impair gametogenesis by reducing the exflagellation of microgametes by 20% at IC90, while tryptanthrin and T8 had no influence on exflagellation. The results of this study confirm that tryptanthrin and its derivatives are potential antimalarial candidates with abilities to kill the intraerythrocytic asexual stages and prevent the formation of sexual stages of the parasite. PMID:25949928

Synthesis and evaluation of the antiplasmodial activity of tryptanthrin derivatives.

PubMed

Onambele, Liliane Abodo; Riepl, Herbert; Fischer, Rainer; Pradel, Gabriele; Prokop, Aram; Aminake, Makoah Nigel

2015-08-01

Malaria remains one of the most deadly diseases threatening humankind and is still affecting a significant proportion of the world population, especially in Africa. Chemotherapy is a vital component of the fight against the disease and new antimalarial agents are urgently needed to curb the spread of malaria parasites that are resistant to existing drugs. The natural product tryptanthrin is known for its wide range of activities, including antiplasmodial activity, but its poor solubility has undermined its development as potent antimicrobial and antiprotozoan agent. The aim of this work was to synthesize analogues of tryptanthrin and to evaluate their antiplasmodial activity against the asexual and sexual blood stages of Plasmodium falciparum. Our results suggest that most tryptanthrin analogues retained their antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant malaria parasites in the nanomolar range (30-100 nM). The antiplasmodial activity of the most active compound NT1 (IC50: 30 nM; SI: 155.9) was similar in both strains and close to that of chloroquine (IC50: 20 nM) on the sensitive strain. The antiplasmodial activity was improved with derivatization, thus pointing out the necessity to explore tryptanthrin using medicinal chemistry approaches. Ten (10) of the tested derivatives met the criteria, allowing for advancement to animal testing, i.e., SI > 100 and IC50 < 100 nM. In addition to their activity on the asexual stages, tryptanthrin and two selected derivatives (NT1 and T8) prevented the maturation of gametocytes at their IC90 concentrations, indicating a transmission-blocking potential. Moreover, NT1 was able to impair gametogenesis by reducing the exflagellation of microgametes by 20% at IC90, while tryptanthrin and T8 had no influence on exflagellation. The results of this study confirm that tryptanthrin and its derivatives are potential antimalarial candidates with abilities to kill the intraerythrocytic asexual stages and prevent the formation of sexual stages of the parasite.

Antiplasmodial Properties and Bioassay-Guided Fractionation of Ethyl Acetate Extracts from Carica papaya Leaves

PubMed Central

Melariri, Paula; Campbell, William; Etusim, Paschal; Smith, Peter

2011-01-01

We investigated the antiplasmodial properties of crude extracts from Carica papaya leaves to trace the activity through bioassay-guided fractionation. The greatest antiplasmodial activity was observed in the ethyl acetate crude extract. C. papaya showed a high selectivity for P. falciparum against CHO cells with a selectivity index of 249.25 and 185.37 in the chloroquine-sensitive D10 and chloroquine-resistant DD2 strains, respectively. Carica papaya ethyl acetate extract was subjected to bioassay-guided fractionation to ascertain the most active fraction, which was purified and identified using high-pressure liquid chromatography (HPLC) and GC-MS (Gas chromatography-Mass spectrometry) methods. Linoleic and linolenic acids identified from the ethyl acetate fraction showed IC50 of 6.88 μg/ml and 3.58 μg/ml, respectively. The study demonstrated greater antiplasmodial activity of the crude ethyl acetate extract of Carica papaya leaves with an IC50 of 2.96 ± 0.14 μg/ml when compared to the activity of the fractions and isolated compounds. PMID:22174990

Antiplasmodial potential of traditional phytotherapy of some remedies used in treatment of malaria in Meru-Tharaka Nithi County of Kenya.

PubMed

Muthaura, C N; Keriko, J M; Mutai, C; Yenesew, Abiy; Gathirwa, J W; Irungu, B N; Nyangacha, R; Mungai, G M; Derese, Solomon

2015-12-04

Medicinal plants play a major role in many communities across the world, in the treatment and prevention of disease and the promotion of general health. The aim of the study was to escalate documentation from an earlier study of medicinal plants, traditionally used to combat malaria by the Ameru community of Imenti Forest area and Gatunga in Eastern Region of Kenya, and validate their ethnopharmacological claims by evaluating their antiplasmodial efficacies. The study was carried out in Meru County at Imenti Forest Game Reserve and in Tharaka Nithi County at Gatunga. Traditional health practitioners (THP) were interviewed with a standard questionnaire to obtain information on medicinal plants traditionally used for management of malaria. Group interviews were also held among THPs and members of the community. The antiplasmodial activities of the crude extracts against chloroquine sensitive (D6) and resistant (W2) Plasmodium falciparum were determined using the semi-automated micro-dilution technique that measures the ability of the extracts to inhibit the incorporation of (G-3H) hypoxanthine into the malaria parasite. Ninety nine (99) species in eighty one (81) genera and forty five (45) families were documented and evaluated for in vitro antiplasmodial activity. Compositae, Fabaceae, Meliceae, Rubiaceae, Rutaceae and Verbenaceae had the highest number of species mentioned in treatment of malaria in Meru/Tharaka Nithi study area. Twenty four (24.2%) species showed antiplasmodial efficacy of IC50 ≤ 5 µg/ml and were considered to have potential for isolation of antimalarial compounds. Eight plant (8) species with moderate antiplasmodial activity namely; Cordia africana, Commiphora africana, Elaeodendron buchananii, Gomphocarpus semilunatus, Tarena graveolens, Plectranthus igniarius, Acacia senegal and Ziziphus abyssinica were documented from this region for the first time for the treatment of malaria. The antiplasmodial activity of MeOH root bark extract of Maytenus obtusifolia was very promising (IC50 < 1.9 µg/ml) and this is the first report on traditional use of M. obtusifolia for treatment of malaria and antimalarial activity. The results seem to indicate that ethnopharmacological inquiry used in search for new herbal remedies as predictive and could be used as the basis for search of new active principles. Eight plant (8) species are documented from this region for the first time for the treatment of malaria. This is the first report on traditional use of M. obtusifolia for treatment of malaria and evaluation of its antiplasmodial activity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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

PubMed

Jansen, Olivia; Tchinda, Alembert T; Loua, Jean; Esters, Virginie; Cieckiewicz, Ewa; Ledoux, Allison; Toukam, Paul D; Angenot, Luc; Tits, Monique; Balde, Aliou M; Frédérich, Michel

2017-05-05

Decoctions 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. To evaluate the in vitro antiplasmodial activity and to identify active compounds from extracts of M. benthamianum leaves. Antiplasmodial 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. Hydroethanolic extracts (70% v/v) of M. benthamianum leaves showed a moderate in vitro activity against P. falciparum 3D7, with IC 50 in the range 22.5 - 32.6µg/mL, depending on the batch; while a dark precipitate formed during ethanol evaporation showed higher activity (IC 50 =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). This 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. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Norepinephrine alkaloids as antiplasmodial agents: Synthesis of syncarpamide and insight into the structure-activity relationships of its analogues as antiplasmodial agents.

PubMed

Aratikatla, Eswar K; Valkute, Tushar R; Puri, Sunil K; Srivastava, Kumkum; Bhattacharya, Asish K

2017-09-29

Syncarpamide 1, a norepinephrine alkaloid isolated from the leaves of Zanthoxylum syncarpum (Rutaceae) exhibited promising antiplasmodial activities against Plasmodium falciparum with reported IC 50 values of 2.04 μM (D6 clone), 3.06 μM (W2 clone) and observed by us 3.90 μM (3D7 clone) and 2.56 μM (K1 clone). In continuation of our work on naturally occurring antimalarial compounds, synthesis of syncarpamide 1 and its enantiomer, (R)-2 using Sharpless asymmetric dihydroxylation as a key step has been accomplished. In order to study structure-activity-relationship (SAR) in detail, a library of 55 compounds (3-57), which are analogues/homologues of syncarpamide 1 were synthesized by varying the substituents on the aromatic ring, by changing the stereocentre at the C-7 and/or by varying the acid groups in the ester and/or amide side chain based on the natural product lead molecule and further assayed in vitro against 3D7 and K1 strains of P. falciparum to evaluate their antiplasmodial activities. In order to study the effect of position of functional groups on antiplasmodial activity profile, a regioisomer (S)-58 of syncarpamide 1 was synthesized however, it turned out to be inactive against both the strains. Two compounds, (S)-41 and its enantiomer, (R)-42 having 3,4,5-trimethoxy cinnamoyl groups as side chains showed better antiplasmodial activity with IC 50 values of 3.16, 2.28 μM (3D7) and 1.78, 2.07 μM (K1), respectively than the natural product, syncarpamide 1. Three compounds (S)-13, (S)-17, (S)-21 exhibited antiplasmodial activities with IC 50 values of 6.39, 6.82, 6.41 μM against 3D7 strain, 4.27, 7.26, 2.71 μM against K1 strain and with CC 50 values of 147.72, 153.0, >200 μM respectively. The in vitro antiplasmodial activity data of synthesized library suggests that the electron density and possibility of resonance in both the ester and amide side chains increases the antiplasmodial activity as compared to the parent natural product 1. The natural product syncarpamide 1 and four analogues/homologues out of the synthesized library of 55, (S)-41, (R)-42, (S)-55 and (S)-57 were assayed in vivo assay against chloroquine-resistant P. yoelii (N-67) strain of Plasmodium. However, none of the five molecules, 1, (S)-41, (R)-42, (S)-55 and (S)-57 exhibited any promising in vivo antimalarial activity against P. yoelii (N-67) strain. Compounds 4, 6, 7 and 11 showed high cytotoxicities with CC 50 values of 5.87, 5.08, 6.44 and 14.04 μM, respectively. Compound 6 was found to be the most cytotoxic as compared to the standard drug, podophyllotoxin whereas compounds 4 and 7 showed comparable cytotoxicities to podophyllotoxin. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

In Vitro Antiplasmodial Activity of Phospholipases A2 and a Phospholipase Homologue Isolated from the Venom of the Snake Bothrops asper

PubMed Central

Castillo, Juan Carlos Quintana; Vargas, Leidy Johana; Segura, Cesar; Gutiérrez, José María; Pérez, Juan Carlos Alarcón

2012-01-01

The antimicrobial and antiparasite activity of phospholipase A2 (PLA2) from snakes and bees has been extensively explored. We studied the antiplasmodial effect of the whole venom of the snake Bothrops asper and of two fractions purified by ion-exchange chromatography: one containing catalytically-active phospholipases A2 (PLA2) (fraction V) and another containing a PLA2 homologue devoid of enzymatic activity (fraction VI). The antiplasmodial effect was assessed on in vitro cultures of Plasmodium falciparum. The whole venom of B. asper, as well as its fractions V and VI, were active against the parasite at 0.13 ± 0.01 µg/mL, 1.42 ± 0.56 µg/mL and 22.89 ± 1.22 µg/mL, respectively. Differences in the cytotoxic activity on peripheral blood mononuclear cells between the whole venom and fractions V and VI were observed, fraction V showing higher toxicity than total venom and fraction VI. Regarding toxicity in mice, the whole venom showed the highest lethal effect in comparison to fractions V and VI. These results suggest that B. asper PLA2 and its homologue have antiplasmodial potential. PMID:23242318

Antimalarial activity of medicinal plants from the Democratic Republic of Congo: A review.

PubMed

Memvanga, Patrick B; Tona, Gaston L; Mesia, Gauthier K; Lusakibanza, Mariano M; Cimanga, Richard K

2015-07-01

Malaria is the most prevalent parasitic disease and the foremost cause of morbidity and mortality in the Democratic Republic of Congo. For the management of this disease, a large Congolese population recourses to traditional medicinal plants. To date the efficacy and safety of many of these plants have been validated scientifically in rodent malaria models. In order to generate scientific evidence of traditional remedies used in the Democratic Republic of Congo for the management of malaria, and show the potential of Congolese plants as a major source of antimalarial drugs, this review highlights the antiplasmodial and toxicological properties of the Congolese antimalarial plants investigated during the period of 1999-2014. In doing so, a useful resource for further complementary investigations is presented. Furthermore, this review may pave the way for the research and development of several available and affordable antimalarial phytomedicines. In order to get information on the different studies, a Google Scholar and PubMed literature search was performed using keywords (malaria, Congolese, medicinal plants, antiplasmodial/antimalarial activity, and toxicity). Data from non-indexed journals, Master and Doctoral dissertations were also collected. Approximately 120 extracts and fractions obtained from Congolese medicinal plants showed pronounced or good antiplasmodial activity. A number of compounds with interesting antiplasmodial properties were also isolated and identified. Some of these compounds constituted new scaffolds for the synthesis of promising antimalarial drugs. Interestingly, most of these extracts and compounds possessed high selective activity against Plasmodium parasites compared to mammalian cells. The efficacy and safety of several plant-derived products was confirmed in mice, and a good correlation was observed between in vitro and in vivo antimalarial activity. The formulation of several plant-derived products also led to some clinical trials and license of three plant-derived drugs (Manalaria(®), Nsansiphos(®), and Quinine Pharmakina(®)). The obtained results partly justify and support the use of various medicinal plants to treat malaria in folk medicine in the Democratic Republic of Congo. Antimalarial plants used in Congolese traditional medicine represent an important source for the discovery and development of new antimalarial agents. However, in order to ensure the integration of a larger number of plant-derived products in the Congolese healthcare system, some parameters and trends should be considered in further researches, in agreement with the objectives of the "Traditional Medicine Strategy" proposed by the World Health Organization in 2013. These include evaluation of geographical and seasonal variation, investigation of reproductive biology, assessment of prophylactic antimalarial activity, evaluation of natural products as adjuvant antioxidant therapy for malaria, development of plant-based combination therapies and monitoring of herbal medicines in pharmacovigilance systems. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Antiplasmodial activities and cytotoxic effects of aqueous extracts and sesquiterpene lactones from Neurolaena lobata.

PubMed

François, G; Passreiter, C M; Woerdenbag, H J; Van Looveren, M

1996-04-01

Aqueous and lipophilic extracts of Neurolaena lobata (Asteraceae), obtained from Guatemala, were tested against Plasmodium falciparum in vitro. Moreover, sesquiterpene lactones, of the germacranolide and furanoheliangolide type, isolated from N. lobata, were shown to be active against P. falciparum in vitro. In addition to their antiplasmodial activity, their cytotoxic effects on human carcinoma cell lines were evaluated. Structure-activity relationships are discussed.

Benzoheterocyclic amodiaquine analogues with potent antiplasmodial activity: synthesis and pharmacological evaluation.

PubMed

Ongarora, Dennis S B; Gut, Jiri; Rosenthal, Philip J; Masimirembwa, Collen M; Chibale, Kelly

2012-08-01

The synthesis and evaluation of antiplasmodial activity of benzothiazole, benzimidazole, benzoxazole and pyridine analogues of amodiaquine is hereby reported. Benzothiazole and benzoxazole analogues with a protonatable tertiary nitrogen atom possessed excellent activity against the W2 and K1 chloroquine resistant strains of Plasmodium falciparum, with IC(50)s ranging from 7 to 22 nM. Copyright © 2012 Elsevier Ltd. All rights reserved.

Antiplasmodial activity of four Kenyan medicinal plants.

PubMed

Omulokoli, E; Khan, B; Chhabra, S C

1997-04-01

A preliminary antiplasmodial and phytochemical screening of four Kenyan medicinal plants was carried out. The medicinal plants were extracted and tested for in vitro antiplasmodial activity against chloroquine-sensitive (K67) and chloroquine-resistant (ENT36) strains of Plasmodium falciparum. Out of 16 extracts, 12 were active against ENT36 strain while seven were active against K67 strain, that is, IC50 < or = 50 micrograms/ml. The most active extracts on both strains were those of leaves of Phyllanthus reticulatus Poir, and Suregada zanzibariensis Baill. (Euphorbiaceae) with IC50 < or = 10 micrograms/ml. The stembark of Terminalia spinosa Engl. (Combretaceae) and the stems of Dissotis brazzae Cogn. (Melastomataceae) had IC50 < or = 10 micrograms/ml for strains K67 and ENT36, respectively. A preliminary phytochemical analysis of these plants revealed the presence of different classes of primary and secondary metabolites.

Both plants Sebastiania chamaelea from Niger and Chrozophora senegalensis from Senegal used in African traditional medicine in malaria treatment share a same active principle.

PubMed

Garcia-Alvarez, M-C; Moussa, I; Njomnang Soh, P; Nongonierma, R; Abdoulaye, A; Nicolau-Travers, M-L; Fabre, A; Wdzieczak-Bakala, J; Ahond, A; Poupat, C; Ikhiri, K; Benoit-Vical, F

2013-10-07

Based on ethnobotanical data obtained from Nigerien and Senegalese traditional healers, two Euphorbiaceae plants, Sebastiania chamaelea and Chrozophora senegalensis, traditionally used to treat malaria, were selected for further investigations. Plant extracts were prepared with different solvents and tested both in vitro on several strains of Plasmodium falciparum, and in vivo to evaluate their antiplasmodial properties and isolate their active principles. With IC50 values around 6.5µg/ml and no significant cytotoxicity (>50µg/ml), the whole plant aqueous extract from S. chamaelea showed the best in vitro results. In vitro potentiation assays showed strong synergistic activity of S. chamaelea extract with the antiplasmodial drug chloroquine on the chloroquine-resistant P. falciparum strain W2-Indochina. In other respects, the aqueous crude extract of C. senegalensis leaves showed the most significant antiplasmodial activity in vitro (IC50 values less than 2µg/ml). We also demonstrated the prophylactic activity of C. senegalensis in vivo in a murine malaria model. Bioassay-guided fractionation of aqueous extracts of these plants enabled the isolation and identification of ellagic acid (EA, 1) as the main compound responsible for their antiplasmodial activity. Together with EA, other derivatives belonging to different chemical groups were isolated but showed moderate antimalarial activity: gallic acid (2), brevifolin carboxylic acid (3), protocatechuic acid (4), corillagin (5), rutin (6) and 3,4,8,9,10-pentahydroxy-dibenzo(b,d)pyran-6-one (7). The structures were determined by the usual spectroscopic methods and by comparison with published data. Furthermore, we report here the quantification of compound 1 (EA) by RP-HPLC in the dried extracts of these plants, reported for the first time in both these species, and possessing the highest in vitro antiplasmodial activity with IC50 values from 180 to 330nm. These in vitro and in vivo results support the traditional use in Africa of crude extracts of both S. chamaelea and C. senegalensis as an antimalarial treatment and prove the significant antiplasmodial property of EA. © 2013 Elsevier Ireland Ltd. All rights reserved.

Antiplasmodial activity of flavonoids from Macaranga tanarius leaves

NASA Astrophysics Data System (ADS)

Marliana, E.; Hairani, R.; Tjahjandarie, T. S.; Tanjung, M.

2018-04-01

Malaria is one of the leading causes of death in the world which is caused by Plasmodium sp. This parasite tends to have mutation and shows resistance towards malaria drug. Due to the emergence and spread of Plasmodium sp. resistance towards malaria drugs, an exploration to find new effective and selective malaria drug is essential. In this study, four flavonoids, namely nymphaeol C (1), solophenol D (2), nymphaeol A (3), and nymphaeol B (4) were isolated from ethyl acetate fraction of Macaranga tanarius leaves. The structures of those compounds were characterized by NMR analysis. Furthermore, antiplasmodial activity of ethyl acetate fraction and four isolated compounds (1–4) were evaluated by Giemsa method against Plasmodium falciparum strain 3D7. According to this assay, it showed the IC50 values were 0.30, 0.24, 0.31, 0.05, and 0.05 μg/mL, respectively. The results provide important evidence of the antiplasmodial activity of flavonoids in traditional use. In addition, it can be indicated that Macaranga tanarius is potential to be developed as antiplasmodial agents.

In vitro and in vivo anti-plasmodial activity of essential oils, including hinokitiol.

PubMed

Fujisaki, Ryuichi; Kamei, Kiyoko; Yamamura, Mariko; Nishiya, Hajime; Inouye, Shigeharu; Takahashi, Miki; Abe, Shigeru

2012-03-01

Abstract. The anti-plasmodial activity of 47 essential oils and 10 of their constituents were screened for in vitro activity against Plasmodium falciparum. Five of these essential oils (sandalwood, caraway, monarda, nutmeg, and Thujopsis dolabrata var. hondai) and 2 constituents (thymoquinone and hinokitiol) were found to be active against P. falciparum in vitro, with 50% inhibitory concentration (IC50) values equal to or less than 1.0 microg/ml. Furthermore, in vivo analysis using a rodent model confirmed the anti-plasmodial potential of subcutaneously administered sandalwood oil, and percutaneously administered hinokitiol and caraway oil against rodent P. berghei. Notably, these oils showed no efficacy when administered orally, intraperitoneally or intravenously. Caraway oil and hinokitiol dissolved in carrier oil, applied to the skin of hairless mice caused high levels in the blood, with concentrations exceeding their IC50 values.

In vitro and in vivo antimalarial and cytotoxic activity of five plants used in congolese traditional medicine.

PubMed

Lusakibanza, M; Mesia, G; Tona, G; Karemere, S; Lukuka, A; Tits, M; Angenot, L; Frédérich, M

2010-06-16

The in vitro antiplasmodial activity and cytotoxicity of methanolic and dichloromethane extracts from five Congolese plants were evaluated. The plants were selected following an ethnobotanical survey conducted in D.R. Congo and focusing on plants used traditionally to treat malaria. The in vivo antimalarial activity of aqueous and methanolic extracts active in vitro was also determined in mice infected by Plasmodium berghei berghei. The growth inhibition of Plasmodium falciparum strains was evaluated using the measurement of lactate dehydrogenase activity. The extracts (aqueous, CH(3)OH, EtOH and CH(2)Cl(2)) were prepared by maceration and tested in vitro against the 3D7 (chloroquine sensitive) and W2 (chloroquine resistant) strains of Plasmodium falciparum and against the human normal fetal lung fibroblasts WI-38 to determine the selectivity index. Some extracts were also used at the dose of 300 mg/kg to evaluate their activity in mice infected since 4 days by Plasmodium berghei. Two plants presented a very high activity (IC(50)<3 microg/ml). These plants were Strychnos icaja roots bark (MeOH and CH(2)Cl(2)) and Physalis angulata leaves (MeOH and CH(2)Cl(2)). One plant (Anisopappus chinensis whole plant, MeOH and CH(2)Cl(2)) presented a high activity (IC50<15 microg/ml). The extracts of Anisopappus chinensis and Physalis angulata showed also a good inhibition of parasitemia in vivo. Flavonoids, phenolic acids and terpenes were identified in these plants by a general phytochemical screening method. Three plants showed a very interesting antiplasmodial activity (Anisopappus chinensis, Physalis angulata and Strychnos icaja) and one of them showed a good selectivity index (>10, Anisopappus chinensis). Anisopappus chinensis and Physalis angulata were also active in vivo. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Antiplasmodial and Cytotoxic Activity of Raw Plant Extracts as Reported by Knowledgeable Indigenous People of the Amazon Region (Vaupés Medio in Colombia).

PubMed

Pabón, Adriana; Ramirez, Otoniel; Ríos, Alexandra; López, Ena; de Las Salas, Briegel; Cardona, Felipe; Blair, Silvia

2016-05-01

The in vitro antiplasmodial activity of 122 raw extracts prepared in ethanol and water from 35 medicinal plants reported by the Cubeo indigenous village of the Amazon region (Vaupés Medio in Colombia) was evaluated for efficacy against 3D7 (sensitive to chloroquine) and FCR-3 (resistant to chloroquine) Plasmodium falciparum strains. Five percent of these extracts presented a significant antiplasmodial activity (< 5 µg/mL) and 83 % of them were not cytotoxic. These findings highlight the importance of investigating traditional medicinal plants implemented by these ancestral communities of the Amazon region as well as their potential to become a source of new drugs against malaria. Georg Thieme Verlag KG Stuttgart · New York.

HPLC-based activity profiling for antiplasmodial compounds in the traditional Indonesian medicinal plant Carica papaya L.

PubMed

Julianti, Tasqiah; De Mieri, Maria; Zimmermann, Stefanie; Ebrahimi, Samad N; Kaiser, Marcel; Neuburger, Markus; Raith, Melanie; Brun, Reto; Hamburger, Matthias

2014-08-08

Leaf decoctions of Carica papaya have been traditionally used in some parts of Indonesia to treat and prevent malaria. Leaf extracts and fraction have been previously shown to possess antiplasmodial activity in vitro and in vivo. Antiplasmodial activity of extracts was confirmed and the active fractions in the extract were identified by HPLC-based activity profiling, a gradient HPLC fractionation of a single injection of the extract, followed by offline bioassay of the obtained microfractions. For preparative isolation of compounds, an alkaloidal fraction was obtained via adsorption on cationic ion exchange resin. Active compounds were purified by HPLC-MS and MPLC-ELSD. Structures were established by HR-ESI-MS and NMR spectroscopy. For compounds 5 and 7 absolute configuration was confirmed by comparison of experimental and calculated electronic circular dichroism (ECD) spectroscopy data, and by X-ray crystallography. Compounds were tested for bioactivity in vitro against four parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum), and in the Plasmodium berghei mouse model. Profiling indicated flavonoids and alkaloids in the active time windows. A total of nine compounds were isolated. Four were known flavonols--manghaslin, clitorin, rutin, and nicotiflorin. Five compounds isolated from the alkaloidal fraction were piperidine alkaloids. Compounds 5 and 6 were inactive carpamic acid and methyl carpamate, while three alkaloids 7-9 showed high antiplasmodial activity and low cytotoxicity. When tested in the Plasmodium berghei mouse model, carpaine (7) did not increase the survival time of animals. The antiplasmodial activity of papaya leaves could be linked to alkaloids. Among these, carpaine was highly active and selective in vitro. The high in vitro activity could not be substantiated with the in vivo murine model. Further investigations are needed to clarify the divergence between our negative in vivo results for carpaine, and previous reports of in vivo activity with papaya leaf extracts. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Ethnomedicinal survey and in vitro anti-plasmodial activity of the palm Borassus aethiopum Mart.

PubMed

Gruca, Marta; Yu, Wanwan; Amoateng, Patrick; Nielsen, Morten Agertoug; Poulsen, Thomas B; Balslev, Henrik

2015-12-04

Malaria remains a major global health threat, with the heaviest burden of disease in sub-Saharan Africa. Effective treatment is not available in many affected areas, and the Plasmodium falciparum parasite is becoming resistant to existing drugs. Alternative therapies are necessary to overcome these challenges. Borassus aethiopum is the third most used palm species in traditional medicines in Africa. Yet, there is only limited information substantiating medicinal properties of the palm. The objective of this study was to document medicinal uses of B. aethiopum and investigate anti-plasmodial activity of the palm extracts used in traditional medicine to treat malaria. The fieldwork and collection of samples was done in Ghana in the Greater Accra, Brong Ahafo, and Volta regions. Our ethnomedicinal survey did not specifically focus on medicinal uses against malaria; any medicinal application of B. aethiopum was of interest. Data collection employed a structured questionnaire, open-ended questions, and group discussion. The experimental extraction of samples was carried out using three common solvents: distilled water, absolute ethanol, and dichloromethane (CH2Cl2). Anti-plasmodial activity of compounds was determined against erythrocytic stages of the FCR3 strain of P. falciparum by a [3H]-hypoxanthine incorporation assay. A total of 37 use records were documented regarding the medicinal uses of B. aethiopum for the management of 24 different disorders. The highest medicinal use value was recorded for the use of B. aethiopum against malaria, and a subsequent laboratory investigation focused on evaluating anti-plasmodial activity of the palm. Several root and leaf extracts displayed anti-plasmodial activity, with the highest (78% at 50 μg/mL) elicited by one of the dichloromethane root extracts. Our results demonstrate the value of integrating ethnobotanical and pharmacological research in the study of beneficial effects of palm products on human health. While the high inhibitory activity found in dichloromethane extracts cannot validate the ethnomedicinal use, the anti-plasmodial effect observed cannot be nullified. We brought preliminary evidence that this palm is a promising source of alternative medicines that could contribute to improving health conditions in malaria endemic areas of sub-Saharan Africa. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Syntheses and in Vitro Antiplasmodial Activity of Aminoalkylated Chalcones and Analogues.

PubMed

Wilhelm, Anke; Kendrekar, Pravin; Noreljaleel, Anwar E M; Abay, Efrem T; Bonnet, Susan L; Wiesner, Lubbe; de Kock, Carmen; Swart, Kenneth J; van der Westhuizen, Jan Hendrik

2015-08-28

A series of readily synthesized and inexpensive aminoalkylated chalcones and diarylpropane analogues (1-55) were synthesized and tested against chloroquinone-sensitive (D10 and NF54) and -resistant (Dd2 and K1) strains of Plasmodium falciparum. Hydrogenation of the enone to a diarylpropane moiety increased antiplasmodial bioactivity significantly. The influence of the structure of the amine moiety, A-ring substituents, propyl vs ethyl linker, and chloride salt formation on further enhancing antiplasmodial activity was investigated. Several compounds have IC₅₀ values similar to or better than chloroquine (CQ). The most active compound (26) had an IC₅₀ value of 0.01 μM. No signs of resistance were detected, as can be expected from compounds with structures unrelated to CQ and other currently used antimalarial drugs. Toxicity tests (in vitro CHO cell assay) gave high SI indices.

Ultraviolet-visible study on acid-base equilibria of aporphine alkaloids with antiplasmodial and antioxidant activities from Alseodaphne corneri and Dehaasia longipedicellata

PubMed Central

Zahari, Azeana; Ablat, Abdulwali; Omer, Noridayu; Nafiah, Mohd Azlan; Sivasothy, Yasodha; Mohamad, Jamaludin; Khan, Mohammad Niyaz; Awang, Khalijah

2016-01-01

The UV-vis spectra of isocorydine 1, norisocorydine 2 and boldine 3 were studied in 2% v/v acetonitrile, at constant ionic strength (0.1 M NaCl, 35 degree Celsius). The pKa values of isocorydine 1 and norisocorydine 2 were 11.75 and 12.07, respectively. Boldine 3 gave a pKa value of 9.16 and 10.44. All of the alkaloids 1–3 were stable at physiological pH; thereby all of them will not ionize, thus permitting the basic nitrogen to be protonated and accumulated within the acidic food vacuole of Plasmodium via pH trapping. Subsequently, acidic food vacuoles that have been neutralized by alkaloids would result in enhancement of the antiplasmodial activity. The alkaloids showed antiplasmodial activity against Plasmodium falciparum and antioxidant activities; DPPH radical scavenging, metal chelating and ferric reducing power. The antioxidant properties of the alkaloids under investigation revealed that in addition to the antiplasmodial activity, the alkaloids can also prevent oxidative damage. It can be prevented by binding free heme and neutralizing the electrons produced during the Plasmodium falciparum mediated haemoglobin destruction in the host. Slightly basic properties of the aforementioned alkaloids, along with their antioxidant activities, are advantageous in improving the suppression of malaria infection that cause less damage to the host. PMID:26898753

The role of hemocytes in A. gambiae antiplasmodial immunity

PubMed Central

Ramirez, Jose Luis; Garver, Lindsey S.; Brayner, Fábio André; Alves, Luiz Carlos; Rodrigues, Janneth; Molina-Cruz, Alvaro; Barillas-Mury, Carolina

2013-01-01

Hemocytes synthesize key components of the mosquito complement-like system, but their role in the activation of antiplasmodial responses has not been established. The effect of activating Toll signaling in hemocytes on Plasmodium survival was investigated by transferring hemocytes or cell-free hemolymph from donor mosquitoes in which the suppressor cactus was silenced. These transfers greatly enhanced antiplasmodial immunity, indicating that hemocytes are active players in the activation of the complement-like system, through an effector(s) regulated by the Toll pathway. A comparative analysis of hemocyte populations between susceptible (S) G3 and the refractory (R) L3-5 A. gambiae mosquito strains did not reveal significant differences under basal conditions or in response to Plasmodium berghei infection. The response of S mosquitoes to different Plasmodium species revealed similar kinetics following infection with P. berghei, P. yoelii or P. falciparum, but the strength of the priming response was stronger in less compatible mosquito-parasite pairs. The Toll, Imd, STAT or JNK signaling cascades were not essential for the production of hemocyte differentiation factor (HDF) in response to P. berghei infection, but disruption of Toll, STAT or JNK abolished hemocyte differentiation in response to HDF. We conclude that hemocytes are key mediators of A. gambiae antiplasmodial responses. PMID:23886925

Evaluation of an ethnopharmacologically selected Bhutanese medicinal plants for their major classes of phytochemicals and biological activities.

PubMed

Wangchuk, Phurpa; Keller, Paul A; Pyne, Stephen G; Taweechotipatr, Malai; Tonsomboon, Aunchalee; Rattanajak, Roonglawan; Kamchonwongpaisan, Sumalee

2011-09-01

As many as 229 medicinal plants have been currently used in the Bhutanese Traditional Medicine (BTM) as a chief ingredient of polyherbal formulations and these plants have been individually indicated for treating various types of infections including malaria, tumor, and microbial. We have focused our study only on seven species of these plants. We aim to evaluate the antiplasmodial, antimicrobial, anti-Trypanosoma brucei rhodesiense and cytotoxicity activities of the seven medicinal plants of Bhutan selected using an ethno-directed bio-rational approach. This study creates a scientific basis for their use in the BTM and gives foundation for further phytochemical and biological evaluations which can result in the discovery of new drug lead compounds. A three stage process was conducted which consisted of: (1) an assessment of a pharmacopoeia and a formulary book of the BTM for their mode of plant uses; (2) selecting 25 anti-infective medicinal plants based on the five established criteria, collecting them, and screening for their major classes of phytochemicals using appropriate test protocols; and (3) finally analyzing the crude extracts of the seven medicinal plants, using the standard test protocols, for their antiplasmodial, antimicrobial, anti-Trypanosoma brucei rhodesiense and cytotoxicity activities as directed by the ethnopharmacological uses of each plant. Out of 25 medicinal plants screened for their major classes of phytochemicals, the majority contained tannins, alkaloids and flavonoids. Out of the seven plant species investigated for their biological activities, all seven of them exhibited mild antimicrobial properties, five plants gave significant in vitro antiplasmodial activities, two plants gave moderate anti-Trypanosoma brucei rhodesiense activity, and one plant showed mild cytotoxicity. Meconopsis simplicifolia showed the highest antiplasmodial activity with IC(50) values of 0.40 μg/ml against TM4/8.2 strain (a wild type chloroquine and antifolate sensitive strain) and 6.39 μg/ml against K1CB1 (multidrug resistant strain) strain. Significantly the extracts from this plant did not show any cytotoxicity. These findings provide the scientific basis for the use of seven medicinal plants in the BTM for the treatment of malaria, microbial infections, infectious fevers, and the Trypanosoma brucei rhodesiense infection. The results also form a good preliminary basis for the prioritization of candidate plant species for further in-depth phytochemical and pharmacological investigations toward our quest to unearth lead antiparasitic, anticancer and antimicrobial compounds. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Antiplasmodial activity of sesquiterpene lactones and a sucrose ester from Vernonia guineensis Benth. (Asteraceae)

PubMed Central

Toyang, Ngeh J.; Krause, Michael A.; Fairhurst, Rick M.; Tane, Pierre; Bryant, Joseph; Verpoorte, Rob

2013-01-01

Ethnopharmacological relevance Aqueous preparations of Vernonia guineensis Benth. (Asteraceae) are used in Cameroonian folk medicine as a general stimulant and to treat various illnesses and conditions including malaria, bacterial infections and helminthic infestations. Materials and methods 10-g samples of the leaf and tuber powders of V. guineensis were extracted separately using dichloromethane, methanol and distilled water. The extracts were dried in vacuo and used in bioassays. These extracts and three compounds previously isolated from V. guineensis [vernopicrin (1), vernomelitensin (2) and pentaisovalerylsucrose (3)] were screened for antiplasmodial activity against chloroquine (CQ)-sensitive (Hb3) and CQ-resistant (Dd2) Plasmodium falciparum lines. Results Crude extracts and pure compounds from V. guineensis showed antiplasmodial activity against both Hb3 and Dd2. The IC50 values of extracts ranged from 1.64 – 27.2 μg/ml for Hb3 and 1.82 – 30.0 μg/ml for Dd2; those for compounds 1, 2 and 3 ranged from 0.47 – 1.62 μg/ml (1364 – 1774 nM) for Hb3 and 0.57 – 1.50 μg/ml (1644 – 2332 nM) for Dd2. None of the crude extracts or pure compounds was observed to exert toxic effects on the erythrocytes used to cultivate the P. falciparum lines. Conclusion In Cameroonian folk medicine, V. guineensis may be used to treat malaria in part due to the antiplasmodial activity of sesquiterpene lactones (1, 2), a sucrose ester (3) and perhaps other compounds present in crude plant extracts. Exploring the safety and antiplasmodial efficacy of these compounds in vivo requires further study. PMID:23542146

Structural characteristics of chloroquine-bridged ferrocenophane analogues of ferroquine may obviate malaria drug-resistance mechanisms.

PubMed

Salas, Paloma F; Herrmann, Christoph; Cawthray, Jacqueline F; Nimphius, Corinna; Kenkel, Alexander; Chen, Jessie; de Kock, Carmen; Smith, Peter J; Patrick, Brian O; Adam, Michael J; Orvig, Chris

2013-02-28

Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (log P) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ∼26.0 Å(2) give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance.

Quinoline hybrids and their antiplasmodial and antimalarial activities.

PubMed

Hu, Yuan-Qiang; Gao, Chuan; Zhang, Shu; Xu, Lei; Xu, Zhi; Feng, Lian-Shun; Wu, Xiang; Zhao, Feng

2017-10-20

Malaria, in particular infection with P. falciparum (the most lethal of the human malaria parasite species, responsible for nearly one million deaths every year), is one of the most devastating and common infectious disease throughout the world. Beginning with quinine, quinoline containing compounds have long been used in clinical treatment of malaria and remained the mainstays of chemotherapy against malaria. The emergence of P. falciparum strains resistant to almost all antimalarials prompted medicinal chemists and biologists to study their effective replacement with an alternative mechanism of action and new molecules. Combination with variety of quinolines and other active moieties may increase the antiplasmodial and antimalarial activities and reduce the side effects. Thus, hybridization is a very attractive strategy to develop novel antimalarials. This review aims to summarize the recent advances towards the discovery of antiplasmodial and antimalarial hybrids including quinoline skeleton to provide an insight for rational designs of more active and less toxic quinoline hybrids antimalarials. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Syncarpamide, a new antiplasmodial (+)-norepinephrine derivative from Zanthoxylum syncarpum.

PubMed

Ross, Samir A; Sultana, Gazi N N; Burandt, Charles L; ElSohly, Mahmoud A; Marais, Jannie P J; Ferreira, Daneel

2004-01-01

A new (+)-norepinephrine derivative, syncarpamide (1), along with a known coumarin, (+)-S-marmesin (2), and one known alkaloid, decarine (3), have been isolated from the stem of Zanthoxylum syncarpum. The structure of compound 1 was elucidated on the basis of 1D and 2D NMR, MS, IR, optical rotation, and CD analyses. Its absolute stereochemistry was elucidated by synthesis of its enantiomer and subsequent comparison of CD data. Characterizations of compounds 2 and 3 were based on spectral analysis and comparison with reported data. Compounds 1 and 3 showed antiplasmodial activity, with IC(50) values of 2.04 and 1.44 microM against Plasmodium falciparum D(6) clone and 3.06 and 0.88 microM against P. falciparum W(2) clone, respectively. Compound 3 showed cytotoxicity at 56.42 microM, whereas compound 1 was not cytotoxic at 10.42 microM. Compound 1 was tested for hypotensive activity, but no activity was observed. Compound 2 showed no antiplasmodial or antimicrobial activities.

Amazonian plants from Peru used by Quechua and Mestizo to treat malaria with evaluation of their activity.

PubMed

Roumy, V; Garcia-Pizango, G; Gutierrez-Choquevilca, A-L; Ruiz, L; Jullian, V; Winterton, P; Fabre, N; Moulis, C; Valentin, A

2007-07-25

Indigenous Quechua and Mestizo populations from distinct areas in Loreto, Peru, were interviewed about traditional medication for the treatment of malaria. An ethnographic survey concerning the native theory of illness aetiology in the specific case of malaria permitted the elaboration of an efficient ethnopharmacological enquiry. The survey took place on three main zones corresponding to villages on the Napo and the Pastaza rivers (for the Quechua), and in the surroundings of Iquitos (for the Mestizos) and led to the collection of 14 plants. Serial extractions in hexane, dichloromethane, and methanol were performed on the different parts of the plants collected. The extracts were then tested for antiplasmodial activity in vitro. Seven plants displayed antiplasmodial activity (IC(50) from 2 to 25 microg/mL) and usually low cytotoxicity, indicating their antiplasmodial specificity. The results give scientific validation to the traditional medical knowledge of Quechua and Mestizo populations from Loreto and confirm a source of potentially active plants.

In vitro antiplasmodial, antiamoebic, and cytotoxic activities of some monomeric isoquinoline alkaloids.

PubMed

Wright, C W; Marshall, S J; Russell, P F; Anderson, M M; Phillipson, J D; Kirby, G C; Warhurst, D C; Schiff, P L

2000-12-01

Twenty-one alkaloids have been assessed for activities against Plasmodium falciparum (multidrug- resistant strain K1) in vitro; 18 of these are reported for the first time. Two protoberberine alkaloids, dehydrodiscretine and berberine, were found to have antiplasmodial IC(50) values less than 1 M, while seven alkaloids-allocrytopine, columbamine, dehydroocoteine, jatrorrhizine, norcorydine, thalifendine, and ushinsunine-had values between 1 and 10 M. These results are discussed in the context of structure-activity relationships. Compounds were also assessed for antiamoebic and cytotoxic activities, but none was significantly active except for berberine, which was moderately cytotoxic.

A search for antiplasmodial metabolites among fungal endophytes of terrestrial and marine plants of southern India.

PubMed

Kaushik, Naveen Kumar; Murali, Thokur Sreepathy; Sahal, Dinkar; Suryanarayanan, T S

2014-10-01

Eighty four different fungal endophytes isolated from sea grasses (5), marine algae (36) and leaves or barks of forest trees (43) were grown in vitro and the secondary metabolites secreted by them were harvested by immobilizing them on XAD beads. These metabolites were eluted with methanol and screened using SYBR Green I assay for their antiplasmodial activity against blood stage Plasmodium falciparum in human red blood cell culture. Our results revealed that fungal endophytes belonging to diverse genera elaborate antiplasmodial metabolites. A Fusarium sp. (580, IC50: 1.94 μg ml(-1)) endophytic in a marine alga and a Nigrospora sp. (151, IC50: 2.88 μg ml(-1)) endophytic in a tree species were subjected to antiplasmodial activity-guided reversed phase high performance liquid chromatography separation. Purification led to potentiation as reflected in IC50 values of 0.12 μg ml(-1) and 0.15 μg ml(-1) for two of the fractions obtained from 580. Our study adds further credence to the notion that fungal endophytes are a potential storehouse for a variety of novel secondary metabolites vested with different bioactivities including some that can stall the growth of the malaria parasite.

Evaluation of the In Vitro Antiplasmodial, Antileishmanial, and Antitrypanosomal Activity of Medicinal Plants Used in Saudi and Yemeni Traditional Medicine

PubMed Central

Mothana, Ramzi A.; Al-Musayeib, Nawal M.; Al-Ajmi, Mohamed F.; Cos, Paul; Maes, Louis

2014-01-01

The antiplasmodial, antileishmanial, and antitrypanosomal activity of twenty-five medicinal plants distributed in Saudi Arabia and Yemen was evaluated. The plants were extracted with methanol and screened in vitro against erythrocytic schizonts of Plasmodium falciparum, intracellular amastigotes of Leishmania infantum and Trypanosoma cruzi, and free trypomastigotes of T. brucei. To assess selectivity, cytotoxicity was determined on MRC-5 cells. Criteria for activity were an IC50 < 10 μg/mL and high selectivity (SI). Seven plants showed interesting antiprotozoal activity in one or more models. Extracts of Caralluma penicillata and Acalypha ciliata showed fairly good activity against P. falciparum with IC50 of 6.7 and 10.8 μg/mL and adequate selectivity (SI > 9.6 and >5.9). Interesting activity against L. infantum was obtained with Verbascum bottae (IC50 of 3.2 μg/mL, SI 10.2) and Solanum glabratum (IC50 8.1 μg/mL, SI 3.4). The extracts of C. penicillata, Leucas virgata, Loranthus regularis, and V. bottae exhibited moderate activity against T. brucei (IC50 8.5, 8.1, 8.3, and 2.3 μg/mL; SI > 7.6, 7.7, 4.3, and >14.1). These results partly support the traditional use of some of the selected medicinal plants and warrant further investigations into the putative active constituents. PMID:24963330

Investigating the activity of quinine analogues versus chloroquine resistant Plasmodium falciparum.

PubMed

Dinio, Theresa; Gorka, Alexander P; McGinniss, Andrew; Roepe, Paul D; Morgan, Jeremy B

2012-05-15

Plasmodium falciparum, the deadliest malarial parasite species, has developed resistance against nearly all man-made antimalarial drugs within the past century. However, quinine (QN), the first antimalarial drug, remains efficacious worldwide. Some chloroquine resistant (CQR) P. falciparum strains or isolates show mild cross resistance to QN, but many do not. Further optimization of QN may provide a well-tolerated therapy with improved activity versus CQR malaria. Thus, using the Heck reaction, we have pursued a structure-activity relationship study, including vinyl group modifications of QN. Certain derivatives show good antiplasmodial activity in QN-resistant and QN-sensitive strains, with lower IC(50) values relative to QN. Copyright © 2012 Elsevier Ltd. All rights reserved.

Synthesis and in vitro antiplasmodial evaluation of 7-chloroquinoline-chalcone and 7-chloroquinoline-ferrocenylchalcone conjugates.

PubMed

Raj, Raghu; Saini, Anu; Gut, Jiri; Rosenthal, Philip J; Kumar, Vipan

2015-05-05

The manuscript describes the synthesis of novel amide tethered 7-chloroquinoline-chalcone and 7-chloroquinoline-ferrocenylchalcone bifunctional hybrids and their evaluation as antimalarial agents against W2 resistant strain of Plasmodium falciparum. The antiplasmodial activity of 7-chloroquinoline-ferrocenylchalcones was found to be less than their corresponding simple chalcone conjugates. The presence of a methoxy substituent at para position of ring B on chalcones and longer alkyl chain length markedly improved the antiplasmodial profiles of the synthesized scaffolds with the most potent of the test compound exhibiting an IC50 value of 17.8 nM. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Antiplasmodial, anti-inflammatory and cytotoxic activities of various plant extracts from the Mascarene Archipelago.

PubMed

Jonville, M C; Kodja, H; Strasberg, D; Pichette, A; Ollivier, E; Frédérich, M; Angenot, L; Legault, J

2011-07-14

Antiplasmodial activity, inhibition of nitric oxide (NO) overproduction, and anti-proliferative activity were investigated in vitro to evaluate the bioactive potential of the traditional pharmacopoeia of the Mascarene Archipelago, which is known for its biodiversity and for the richness of its endemic flora. A total of 45 methanol (MeOH) and dichloromethane (DCM) extracts were prepared from 19 plant species collected on Réunion and Mauritius Islands. Ninety-six-well microplate assays were performed on chloroquine sensitive Plasmodium falciparum 3D7 strain, on LPS-stimulated Raw 264.7 murine macrophages and on A-549, DLD-1 and WS1 human cells. Activity was evaluated through spectrophotometric methods. Activity was attributed to plant extracts expressing IC(50)<50μg/ml for antiplasmodial response, IC(50)<100μg/ml for cytotoxicity, and IC(50)<130μg/ml for anti-inflammatory reaction. The majority of the extracts tested (69%) exhibited potency in at least one of these three types of activity. This is the first report describing promising antiplasmodial activity (IC(50)<15μg/ml) for Psiadia dentata DCM extract and Terminalia bentzoe MeOH bark extract. NO inhibition assay revealed seven interesting plants, described for the first time as anti-inflammatory: Aphloia theiformis, Buddleja salviifolia, Eupatorium riparium, Hiptage benghalensis, Psiadia arguta, Psiadia dentata, and Scutia commersonii. Finally, anti-proliferative activity was observed for two endemic species, Geniostoma borbonicum and Nuxia verticillata. Using the criterion of endemism as part of the criteria for traditional medicinal use raises the chances of finding original active principles. In our case, 86% of the endemic plants tested displayed pharmacological interest. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Screening of selected indigenous plants of Cambodia for antiplasmodial activity.

PubMed

Hout, Sotheara; Chea, Aun; Bun, Sok-Siya; Elias, Riad; Gasquet, Monique; Timon-David, Pierre; Balansard, Guy; Azas, Nadine

2006-08-11

The in vitro antiplasmodial activity of 117 aqueous, methanol and dichloromethane extracts derived from different parts of 28 indigenous wild plant species was studied. These plants are commonly used in Cambodian traditional medicine. The plant extracts were tested for in vitro activity against a chloroquine resistant Plasmodium falciparum strain (W2). Nine extracts were moderately active with IC(50) values ranging between 5 and 10 microg/ml, 17 extracts were active with IC(50) values ranging between 1 and 5 microg/ml. These 26 extracts derived from eight plants belong to six families. The most active extracts were dichloromethane and came from Stephania rotunda and Brucea javanica with IC(50) values of 1 microg/ml and a selectivity index > or = 25. It is interesting to note that some aqueous extracts were as active as dichloromethane extracts especially aqueous extracts of Stephania rotunda, Brucea javanica, Phyllanthus urinaria and Eurycoma longifolia with IC(50) values of < or = 4 microg/ml. These results are in agreement with statements of healers on traditional uses of these plants for the treatment of malaria and/or fever. In this study, we report the antiplasmodial potential activity of eight plant species from Cambodia. Among them four are tested for the first time.

Synthesis, Antiplasmodial Activity, and β-Hematin Inhibition of Hydroxypyridone–Chloroquine Hybrids

PubMed Central

2013-01-01

A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor N-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of Plasmodium falciparum. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were 8c (0.13, 0.004, and 0.1 μM); 8d (0.08, 0.01, and 0.02 μM); and 7g (0.07, 0.03, and 0.08 μM). PMID:24900724

Anti-plasmodial activity of Norcaesalpin D and extracts of four medicinal plants used traditionally for treatment of malaria.

PubMed

Nondo, Ramadhani Selemani Omari; Moshi, Mainen Julius; Erasto, Paul; Masimba, Pax Jessey; Machumi, Francis; Kidukuli, Abdul Waziri; Heydenreich, Matthias; Zofou, Denis

2017-03-24

Malaria is an old life-threatening parasitic disease that is still affecting many people, mainly children living in sub-Saharan Africa. Availability of effective antimalarial drugs played a significant role in the treatment and control of malaria. However, recent information on the emergence of P. falciparum parasites resistant to one of the artemisinin-based combination therapies suggests the need for discovery of new drug molecules. Therefore, this study aimed to evaluate the antiplasmodial activity of extracts, fractions and isolated compound from medicinal plants traditionally used in the treatment of malaria in Tanzania. Dry powdered plant materials were extracted by cold macerations using different solvents. Norcaesalpin D was isolated by column chromatography from dichloromethane root extract of Caesalpinia bonducella and its structure was assigned based on the spectral data. Crude extracts, fractions and isolated compound were evaluated for antiplasmodial activity against chloroquine-sensitive P. falciparum (3D7), chloroquine-resistant P. falciparum (Dd2, K1) and artemisinin-resistant P. falciparum (IPC 5202 Battambang, IPC 4912 Mondolkiri) strains using the parasite lactate dehydrogenase assay. The results indicated that extracts of Erythrina schliebenii, Holarrhena pubescens, Dissotis melleri and C. bonducella exhibited antiplasmodial activity against Dd2 parasites. Ethanolic root extract of E. schliebenii had an IC 50 of 1.87 μg/mL while methanolic and ethanolic root extracts of H. pubescens exhibited an IC 50  = 2.05 μg/mL and IC 50  = 2.43 μg/mL, respectively. Fractions from H. pubescens and C. bonducella roots were found to be highly active against K1, Dd2 and artemisinin-resistant parasites. Norcaesalpin D from C. bonducella root extract was active with IC 50 of 0.98, 1.85 and 2.13 μg/mL against 3D7, Dd2 and IPC 4912-Mondolkiri parasites, respectively. Antiplasmodial activity of norcaesalpin D and extracts of E. schliebenii, H. pubescens, D. melleri and C. bonducella reported in this study requires further attention for the discovery of antimalarial lead compounds for future drug development.

Ferrocene-pyrimidine conjugates: Synthesis, electrochemistry, physicochemical properties and antiplasmodial activities.

PubMed

Chopra, Rakesh; de Kock, Carmen; Smith, Peter; Chibale, Kelly; Singh, Kamaljit

2015-07-15

The promise of hybrid antimalarial agents and the precedence set by the antimalarial drug ferroquine prompted us to design ferrocene-pyrimidine conjugates. Herein, we report the synthesis, electrochemistry and anti-plasmodial evaluation of ferrocenyl-pyrimidine conjugates against chloroquine susceptible NF54 strain of the malaria parasite Plasmodium falciparum. Also their physicochemical properties have been studied. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thiourea isosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites.

PubMed

Verlinden, Bianca K; de Beer, Marna; Pachaiyappan, Boobalan; Besaans, Ethan; Andayi, Warren A; Reader, Janette; Niemand, Jandeli; van Biljon, Riette; Guy, Kiplin; Egan, Timothy; Woster, Patrick M; Birkholtz, Lyn-Marie

2015-08-15

A new series of potent potent aryl/alkylated (bis)urea- and (bis)thiourea polyamine analogues were synthesized and evaluated in vitro for their antiplasmodial activity. Altering the carbon backbone and terminal substituents increased the potency of analogues in the compound library 3-fold, with the most active compounds, 15 and 16, showing half-maximal inhibitory concentrations (IC50 values) of 28 and 30 nM, respectively, against various Plasmodium falciparum parasite strains without any cross-resistance. In vitro evaluation of the cytotoxicity of these analogues revealed marked selectivity towards targeting malaria parasites compared to mammalian HepG2 cells (>5000-fold lower IC50 against the parasite). Preliminary biological evaluation of the polyamine analogue antiplasmodial phenotype revealed that (bis)urea compounds target parasite asexual proliferation, whereas (bis)thiourea compounds of the same series have the unique ability to block transmissible gametocyte forms of the parasite, indicating pluripharmacology against proliferative and non-proliferative forms of the parasite. In this manuscript, we describe these results and postulate a refined structure-activity relationship (SAR) model for antiplasmodial polyamine analogues. The terminally aryl/alkylated (bis)urea- and (bis)thiourea-polyamine analogues featuring a 3-5-3 or 3-6-3 carbon backbone represent a structurally novel and distinct class of potential antiplasmodials with activities in the low nanomolar range, and high selectivity against various lifecycle forms of P. falciparum parasites. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antimicrobial, antiplasmodial, haemolytic and antioxidant activities of crude extracts from three selected Togolese medicinal plants.

PubMed

Karou, Simplice D; Tchacondo, Tchadjobo; Ouattara, Lassina; Anani, Kokou; Savadogo, Aly; Agbonon, Amegnona; Attaia, Mossaclok Ben; de Souza, Comlan; Sakly, Mohsen; Simpore, Jacques

2011-10-01

To investigate the antioxidant, antimicrobial, antiplasmodial, acute toxicity and haemolytic activities of methanolic extracts of three plants. Phytochemical analysis to determine the phenolic contents was also carried out. The 2,2-diphenyl-1-picryl-hydrazyl (DPPH) free radical scavenging, NCCLS broth microdilution and Plasmodium Lactate Dehydrogenase (pLDH) assays were used to determine antioxidant, antimicrobial and antiplasmodial activities, respectively. Haemolysis assay was conducted on A(+) human red blood cells and acute toxicity on male Swiss albino mice. Phenolics were quantitatively determined using spectrophotometric methods. The DPPH assay yielded interesting antioxidant activities of methanolic extract of Parinari curatellifolia (P. curatellifolia) and Entada africana (E. africana) (IC(50) were 0.20±0.01 μg/mL and 0.47±0.01 μg/mL, respectively). This activity was highly correlated with phenolic contents of extracts. The antimicrobial tests displayed minimal inhibitory concentrations (MICs) values ranging from 0.90 to 1.80 mg/mL for Serratia marcescens (S. marcescens) the most susceptible bacterial strain. MIC value was 1.20 mg/mL for susceptible fungal strains including Mucor rouxi (M. rouxi), Fusarium oxyporum (F. oxyporum) and Rhizopus nigricans (R. nigricans). pLDH assay showed moderate antiplasmodial activity of Balanites aegyptiaca (B. aegyptiaca) (IC(50) = 24.56±3.45 μg/mL), however this extract was highly haemolytic and toxic in mice (LD(50) = 625±128 mg/kg). Our results support in part the use of the selected plants in the treatment of microbial infections. In addition the plant showed interesting antioxidant activity that could be useful in the management of oxidative stress. Copyright © 2011 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Design, Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents.

PubMed

Jacobs, Leon; de Kock, Carmen; de Villiers, Katherine A; Smith, Peter J; Smith, Vincent J; van Otterlo, Willem A L; Blackie, Margaret A L

2015-12-01

7-Chloroquinoline-based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine-sensitive (CQS) NF54 (IC50 : 4.2 nm) and chloroquine-resistant (CQR) Dd2 (IC50 : 33.7 nm) strains of P. falciparum. Several compounds were found to have good inhibitory activity against β-hematin formation in an NP-40 detergent assay, with IC50 values ranging between 10.4 and 19.2 μm. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antiplasmodial and anti-inflammatory effects of an antimalarial remedy from the Wayana Amerindians, French Guiana: takamalaimë (Psidium acutangulum Mart. ex DC., Myrtaceae).

PubMed

Houël, Emeline; Fleury, Marie; Odonne, Guillaume; Nardella, Flore; Bourdy, Geneviève; Vonthron-Sénécheau, Catherine; Villa, Pascal; Obrecht, Adeline; Eparvier, Véronique; Deharo, Eric; Stien, Didier

2015-05-26

Field investigations highlighted the use of Psidium acutangulum Mart. ex DC (syn. P. persoonii McVaugh), a small tree used by the Wayana Amerindians in Twenke-Taluhwen and Antecume-Pata, French Guiana, for the treatment of malaria, and administered either orally in the form of a decoction or applied externally over the whole body. This use appears limited to the Wayana cultural group in French Guiana and has never been reported anywhere else. Our goal was to evaluate the antimalarial and anti-inflammatory activities of a P. acutangulum decoction to explain the good reputation of this remedy. Interviews with the Wayana inhabitants of Twenke-Taluhwen and Antecume-Pata were conducted within the TRAMAZ project according to the TRAMIL methodology, which is based on a quantitative and qualitative analysis of medicinal plant uses. A decoction of dried aerial parts of P. acutangulum was prepared in consistency with the Wayana recipe. In vitro antiplasmodial assays were performed on chloroquine-resistant FcB1 ([(3)H]-hypoxanthine bioassay) and 7G8 (pLDH bioassay) P. falciparum strains and on chloroquine sensitive NF54 ([(3)H]-hypoxanthine bioassay) P. falciparum strain. In vitro anti-inflammatory activity (IL-1β, IL-6, IL-8, TNFα) was evaluated on LPS-stimulated human PBMC and NO secretion inhibition was measured on LPS stimulated RAW murine macrophages. Cytotoxicity of the decoction was measured on L6 mammalian cells, PBMCs, and RAW cells. A preliminary evaluation of the in vivo antimalarial activity of the decoction, administered orally twice daily, was assessed by the classical four-day suppressive test against P. berghei NK65 in mice. The decoction displayed a good antiplasmodial activity in vitro against the three tested strains, regardless to the bioassay used, with IC50 values of 3.3µg/mL and 10.3µg/mL against P. falciparum FcB1 and NF54, respectively and 19.0µg/mL against P. falciparum 7G8. It also exhibited significant anti-inflammatory activity in vitro in a dose dependent manner. At a concentration of 50µg/mL, the decoction inhibited the secretion of the following pro-inflammatory cytokines: TNFα (-18%), IL-1β (-58%), IL-6 (-32%), IL-8 (-21%). It also exhibited a mild NO secretion inhibition (-13%) at the same concentration. The decoction was non-cytotoxic against L6 cells (IC50>100µg/mL), RAW cells and PBMC. In vivo, 150µL of the decoction given orally twice a day (equivalent to 350mg/kg/day of dried extract) inhibited 39.7% average parasite growth, with more than 50% of inhibition in three mice over five. The absence of response for the two remaining mice, however, induced a strong standard deviation. This study highlighted the in vitro antiplasmodial activity of the decoction of P. acutangulum aerial parts, used by Wayana Amerindians from the Upper-Maroni in French Guiana in case of malaria. Its antioxidant and anti-inflammatory potential, which may help to explain its use against this disease, was demonstrated using models of artificially stimulated cells. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Analysis of additivity and synergism in the anti-plasmodial effect of purified compounds from plant extracts.

PubMed

Deharo, Eric; Ginsburg, Hagai

2011-03-15

In the search for antimalarials from ethnobotanical origin, plant extracts are chemically fractionated and biological tests guide the isolation of pure active compounds. To establish the responsibility of isolated active compound(s) to the whole antiplasmodial activity of a crude extract, the literature in this field was scanned and results were analysed quantitatively to find the contribution of the pure compound to the activity of the whole extract. It was found that, generally, the activity of isolated molecules could not account on their own for the activity of the crude extract. It is suggested that future research should take into account the "drugs beside the drug", looking for those products (otherwise discarded along the fractionation process) able to boost the activity of isolated active compounds.

Synthesis of novel substituted 1,3-diaryl propenone derivatives and their antimalarial activity in vitro.

PubMed

Mishra, Nidhi; Arora, Preeti; Kumar, Brajesh; Mishra, Lokesh C; Bhattacharya, Amit; Awasthi, Satish K; Bhasin, Virendra K

2008-07-01

The synthesis of novel 1,3-diaryl propenone derivatives and their antimalarial activity in vitro against asexual blood stages of human malaria parasite, Plasmodium falciparum, are described. Chalcone derivatives were prepared via Claisen-Schmidt condensation of substituted aldehydes with substituted methyl ketones. Antiplasmodial IC(50) (half maximal inhibitory concentration) activity of these compounds ranged between 1.5 and 12.3 microg/ml. The chloro-series, 1,2,4-triazole substituted chalcone was found to be the most effective in inhibiting the growth of P. falciparum in vitro while pyrrole and benzotriazole substituted chalcones showed relatively less inhibitory activity. This is the first report on antiplasmodial activity of chalcones with azoles on acetophenone ring.

Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.

PubMed

Ongarora, Dennis S B; Strydom, Natasha; Wicht, Kathryn; Njoroge, Mathew; Wiesner, Lubbe; Egan, Timothy J; Wittlin, Sergio; Jurva, Ulrik; Masimirembwa, Collen M; Chibale, Kelly

2015-09-01

A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

Anti-plasmodial activity of some Zulu medicinal plants and of some triterpenes isolated from them.

PubMed

Simelane, Mthokozisi B C; Shonhai, Addmore; Shode, Francis O; Smith, Peter; Singh, Mogie; Opoku, Andy R

2013-10-08

Mimusops caffra E. Mey. ex A.DC and Mimusops obtusifolia Lam (both members of the Sapotaceae family), and Hypoxis colchicifolia Bak (family Hypoxidaceae) are used by traditional healers in Zululand to manage malaria. Anti-plasmodial investigation of the crude extracts and some triterpenes isolated from the plants showed activity against a chloroquine sensitive (CQS) strain of Plasmodium falciparum (D10). Among the crude extracts the leaves of M. caffra exhibited the highest activity, with an IC₅₀ of 2.14 μg/mL. The pentacyclic tritepenoid ursolic acid (1), isolated from the leaves of M. caffra was the most active compound (IC₅₀ 6.8 μg/mL) as compared to taraxerol (2) and sawamilletin (3) isolated from the stem bark of M. obtusifolia (IC₅₀ > 100). Chemical modification of the ursolic acid (1) to 3β-acetylursolic acid (4) greatly enhanced its anti-plasmodial activity. Compound 4 reduced parasitaemia against Plasmodium berghei by 94.01% in in vivo studies in mice. The cytotoxicity of 3β-acetylursolic acid (IC₅₀) to two human cell lines (HEK293 and HepG2) was 366.00 μg/mL and 566.09 μg/mL, respectively. The results validate the use of these plants in folk medicine.

Antiplasmodial and antimalarial activities of quinolone derivatives: An overview.

PubMed

Fan, Yi-Lei; Cheng, Xiang-Wei; Wu, Jian-Bing; Liu, Min; Zhang, Feng-Zhi; Xu, Zhi; Feng, Lian-Shun

2018-02-25

Malaria remains one of the most deadly infectious diseases globally. Considering the growing spread of resistance, development of new and effective antimalarials remains an urgent priority. Quinolones, which are emerged as one of the most important class of antibiotics in the treatment of various bacterial infections, showed potential in vitro antiplasmodial and in vivo antimalarial activities, making them promising candidates for the chemoprophylaxis and treatment of malaria. This review presents the current progresses and applications of quinolone-based derivatives as potential antimalarials to pave the way for the development of new antimalarials. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Amodiaquine analogues containing NO-donor substructures: synthesis and their preliminary evaluation as potential tools in the treatment of cerebral malaria.

PubMed

Bertinaria, Massimo; Guglielmo, Stefano; Rolando, Barbara; Giorgis, Marta; Aragno, Cristina; Fruttero, Roberta; Gasco, Alberto; Parapini, Silvia; Taramelli, Donatella; Martins, Yuri C; Carvalho, Leonardo J M

2011-05-01

The synthesis and physico-chemical properties of novel compounds obtained by conjugation of amodiaquine with moieties containing either furoxan or nitrooxy NO-donor substructures are described. The synthesised compounds were tested in vitro against both the chloroquine sensitive, D10 and the chloroquine resistant, W-2 strains of Plasmodium falciparum (P. falciparum). Most of the compounds showed an antiplasmodial activity comparable to that of the parent drug. By comparing the activities of simple related structures devoid of the ability to release NO, it appears that the contribution of NO to the antiplasmodial action in vitro is marginal. All the compounds were able to relax rat aorta strips with a NO-dependent mechanism, thus showing their capacity to release NO in the vessels. A preliminary in vivo study using Plasmodium berghei ANKA-infected mice showed a trend for prolonged survival of mice with cerebral malaria treated with compound 40, which is potent and fast amodiaquine-derived NO-donor, when compared with amodiaquine alone or with compound 31, a milder NO-donor. The two compounds showed in vivo antiplasmodial activity similar to that of amodiaquine. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Structure-activity analysis of CJ-15,801 analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation.

PubMed

Spry, Christina; Sewell, Alan L; Hering, Yuliya; Villa, Mathew V J; Weber, Jonas; Hobson, Stephen J; Harnor, Suzannah J; Gul, Sheraz; Marquez, Rodolfo; Saliba, Kevin J

2018-01-01

Survival of the human malaria parasite Plasmodium falciparum is dependent on pantothenate (vitamin B 5 ), a precursor of the fundamental enzyme cofactor coenzyme A. CJ-15,801, an enamide analogue of pantothenate isolated from the fungus Seimatosporium sp. CL28611, was previously shown to inhibit P. falciparum proliferation in vitro by targeting pantothenate utilization. To inform the design of next generation analogues, we set out to synthesize and test a series of synthetic enamide-bearing pantothenate analogues. We demonstrate that conservation of the R-pantoyl moiety and the trans-substituted double bond of CJ-15,801 is important for the selective, on-target antiplasmodial effect, while replacement of the carboxyl group is permitted, and, in one case, favored. Additionally, we show that the antiplasmodial potency of CJ-15,801 analogues that retain the R-pantoyl and trans-substituted enamide moieties correlates with inhibition of P. falciparum pantothenate kinase (PfPanK)-catalyzed pantothenate phosphorylation, implicating the interaction with PfPanK as a key determinant of antiplasmodial activity. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Antiplasmodial activity of flavonol quercetin and its analogues in Plasmodium falciparum: evidence from clinical isolates in Bangladesh and standardized parasite clones.

PubMed

Ganesh, Deepa; Fuehrer, Hans-Peter; Starzengrüber, Peter; Swoboda, Paul; Khan, Wasif Ali; Reismann, Johannes A B; Mueller, Milena S K; Chiba, Peter; Noedl, Harald

2012-06-01

Malaria is still a major threat in many parts of the world with resistance spreading to almost all classes of antimalarials. The limited arsenal of available antimalarial drugs emphasizes the urgent need for novel antimalarial compounds. Owing to the fact that novel leads from nature have traditionally played a pivotal role in the development of various classes of antimalarials, we investigated a set of eight naturally occurring dietary flavonoids and their analogues for their antiplasmodial activity on clinical field isolates in southeastern Bangladesh and culture-adapted chloroquine-sensitive and chloroquine-resistant parasite clones. Except for taxifolin, all the other flavonoids had 50% inhibitory concentrations below 14 μM, both in the field and laboratory-adapted parasites. Neither of the flavonoids showed any activity correlation with chloroquine. The quercetin analogue rutin (7.10 ± 10.32 μM) was the most active substance in field isolates as well as laboratory-adapted cultures (3.53 ± 13.34 μM in 3D7 and 10.38 ± 15.08 μM in K1), providing the first evidence of its activity against Plasmodium falciparum parasites. Thus, our results provide important evidence of the antimalarial activity of flavonoids in traditional use and thus warrant further investigation of these compounds as potential antiplasmodial agents.

Phytochemical investigation of Aloe pulcherrima roots and evaluation for its antibacterial and antiplasmodial activities.

PubMed

Abdissa, Dele; Geleta, Girma; Bacha, Ketema; Abdissa, Negera

2017-01-01

Medicinal plants with documented traditional uses remain an important source for the treatment of a wide range of ailments. Evidence shows that majority of the Ethiopian population are still dependent on traditional medicine. Aloe pulcherrima Gilbert & Sebsebe is one of the endemic Aloe species traditionally used for the treatment of malaria and wound healing in central, Southern and Northern part of Ethiopia. The aim of the current study was, therefore, to isolate active compounds from roots of A. pulcherrima and evaluate for their antibacterial and antiplasmodial activities using standard test strains. Bioassay-guided sequential extraction and column chrom-atographic separation were employed for the isolation of bioactive pure compounds. The structures of the compounds were determined by 1D and 2D NMR spectro-scopic techniques. Disk diffusion method was employed to evaluate the antibacterial activities of the isolated compounds against four bacterial strains specifically (Staphylococcus aureus ATCC 25923, Bacillus subtilis ATCC 6633, Escherichia coli ATCC 35218, Pseudomonas aeruginosa ATCC 27853). The malaria SYBR Green I-based in vitro assay technique was used for in vitro antiplasmodial activity evaluation of the compounds against chloroquine resistant (D6) and -sensitive (W2) strains of P. falciparum. Three compounds, chrysophanol, aloesaponarin I and aloesaponarin II were isolated from the acetone extracts of roots of A. pulcherrima. Evaluation of antibacterial activities revealed that aloesaponarin I and aloesaponarin II had significant activities against all the bacterial strains with inhibition zone diameters ranging from 18-27 mm as compared to the reference drug (gentamicin), which displayed inhibition zone diameter ranging between 20 mm (B. subtilis) and 25 mm (P. aeruginosa). The isolated compounds showed moderate in vitro antiplasmodial activity against both chloroquine resistant (W2) -sensitive (D6) strains. Isolation of chrysophanol, aloesaponarin I and aloesaponarin II from roots of A. pulcherrima is the first report of its kind. The finding could be used for further comprehensive evaluation of the isolated compounds for their antibacterial and antimalarial activities besides consideration of the same for potent drug development.

Part 1: Antiplasmodial, cytotoxic, radical scavenging and antioxidant activities of Thai plants in the family Acanthaceae.

PubMed

Charoenchai, Panarat; Vajrodaya, Srunya; Somprasong, Winai; Mahidol, Chulabhorn; Ruchirawat, Somsak; Kittakoop, Prasat

2010-11-01

Crude extracts (CH(2)Cl(2) and MeOH) of 20 plants in the family Acanthaceae were screened for their antiplasmodial, cytotoxic, antioxidant, and radical scavenging activities. These plants included Asystasia nemorum, Barleria cristata, B. strigosa, Dicliptera burmanni, Eranthemum tetragonum, Hygrophila ringens, Justicia balansae, J. procumbens, Lepidagathis incurva, Peristrophe lanceolaria, Phaulopsis dorsiflora, Ruellia kerrii, Strobilanthes auriculata, S. corrugata, S. cusia, S. dimorphotricha, S. karensium, S. maxwellii, S. pateriformis, and S. brandisii. CH(2)Cl(2) extracts of A. nemorum, S. corrugata, S. cusia, S. maxwellii, S. pateriformis, and S. brandisii, as well as MeOH extracts of J. balansae and J. procumbens, showed antiplasmodial activity with IC(50) values of 10-100 µg/mL. CH(2)Cl(2) extracts of nine plants including D. burmanni, H. ringens, J. balansae, J. procumbens, L. incurva, P. lanceolaria, P. dorsiflora, S. corrugata, and S. maxwellii showed cytotoxic activity with IC(50) values of 3.5-46.0 µg/mL. MeOH extracts (at 100 µg/mL) of R. kerrii and S. auriculata could effectively scavenge DPPH free radicals (82-83% inhibition) and superoxide anion radicals (79% and 88% inhibition). In the ORAC antioxidant assay, MeOH extracts of B. cristata, J. procumbens, R. kerrii, and S. auriculata exhibited activity with ORAC units of 3.1-3.9. © Georg Thieme Verlag KG Stuttgart · New York.

The antimalarial activity of Ru–chloroquine complexes against resistant Plasmodium falciparum is related to lipophilicity, basicity, and heme aggregation inhibition ability near water/n-octanol interfaces

PubMed Central

Martínez, Alberto; Rajapakse, Chandima S. K.; Jalloh, Dalanda; Dautriche, Cula

2012-01-01

We have measured water/n-octanol partition coefficients, pKa values, heme binding constants, and heme aggregation inhibition activity of a series of ruthenium–πarene–chloroquine (CQ) complexes recently reported to be active against CQ-resistant strains of Plasmodium falciparum. Measurements of heme aggregation inhibition activity of the metal complexes near water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ; we conclude that this modified method may be a better predictor of antimalarial potency than standard tests in aqueous acidic buffer. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied. PMID:19343380

The antimalarial activity of Ru-chloroquine complexes against resistant Plasmodium falciparum is related to lipophilicity, basicity, and heme aggregation inhibition ability near water/n-octanol interfaces.

PubMed

Martínez, Alberto; Rajapakse, Chandima S K; Jalloh, Dalanda; Dautriche, Cula; Sánchez-Delgado, Roberto A

2009-08-01

We have measured water/n-octanol partition coefficients, pK(a) values, heme binding constants, and heme aggregation inhibition activity of a series of ruthenium-pi-arene-chloroquine (CQ) complexes recently reported to be active against CQ-resistant strains of Plasmodium falciparum. Measurements of heme aggregation inhibition activity of the metal complexes near water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ; we conclude that this modified method may be a better predictor of antimalarial potency than standard tests in aqueous acidic buffer. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied.

Helichrysum gymnocephalum essential oil: chemical composition and cytotoxic, antimalarial and antioxidant activities, attribution of the activity origin by correlations.

PubMed

Afoulous, Samia; Ferhout, Hicham; Raoelison, Emmanuel Guy; Valentin, Alexis; Moukarzel, Béatrice; Couderc, François; Bouajila, Jalloul

2011-09-29

Helichrysum gymnocephalum essential oil (EO) was prepared by hydrodistillation of its leaves and characterized by GC-MS and quantified by GC-FID. Twenty three compounds were identified. 1,8-Cineole (47.4%), bicyclosesquiphellandrene (5.6%), γ-curcumene (5.6%), α-amorphene (5.1%) and bicyclogermacrene (5%) were the main components. Our results confirmed the important chemical variability of H. gymnocephalum. The essential oil was tested in vitro for cytotoxic (on human breast cancer cells MCF-7), antimalarial (Plasmodium falciparum: FcB1-Columbia strain, chloroquine-resistant) and antioxidant (ABTS and DPPH assays) activities. H. gymnocephalum EO was found to be active against MCF-7 cells, with an IC(50) of 16 ± 2 mg/L. The essential oil was active against P. falciparum (IC(50) = 25 ± 1 mg/L). However, the essential oil exhibited a poor antioxidant activity in the DPPH (IC(50) value > 1,000 mg/L) and ABTS (IC(50) value = 1,487.67 ± 47.70 mg/L) assays. We have reviewed the existing results on the anticancer activity of essential oils on MCF-7 cell line and on their antiplasmodial activity against the P. falciparum. The aim was to establish correlations between the identified compounds and their biological activities (antiplasmodial and anticancer). β-Selinene (R² = 0.76), α-terpinolene (R² = 0.88) and aromadendrene (R² = 0.90) presented a higher relationship with the anti-cancer activity. However, only calamenene (R² = 0.70) showed a significant correlation for the antiplasmodial activity.

Antinociceptive and antiplasmodial activities of cassane furanoditerpenes from Caesalpinia volkensii H. root bark.

PubMed

Ochieng', Charles O; Owuor, P Okinda; Mang'uro, Lawrence A O; Akala, Hosea; Ishola, Ismail O

2012-01-01

The chloroform and ethyl acetate extract (100mg/kg) of Caesalpinia volkensii H. exhibited significant (P ≤ 0.05) antinociceptive activities using hot plate and writhing tests in mice while the later showed antiplasmodial activity (IC(50) 0.23 ± 0.07 and 4.39 ± 2.49 μg/ml) against chloroquine sensitive (D6) and chloroquine-resistant (W2), respectively. Two new furanoditerpenes [rel. 1β,5α-dihydroxyvoucapane (1) and rel. 1β,6β-dihydroxyvoucapane; 19β-methyl ester (2)] together with seven known compounds [voucapane (3), voucapan-5-ol (4), deoxycaesaldekarin C (5), caesaldekarin C (6), 5-hydroxyvinhaticoic acid (7), triacontanyl-(E)-ferulate (8), triacontanyl-(E)-caffaete (9) and 30'-hydroxytriacontanyl-(E)-ferulate (10)] were isolated from the two extracts. The administration of 3, 4, 5 and 6 (100mg/kg i.p) caused a significant (P ≤ 0.05) reduction in the number of writhing episodes induced by acetic acid and (P ≤ 0.01) increased pain latency threshold in hot-plate test compared to control. However, the pure compounds indicated relatively (P ≤ 0.05) low antiplasmodial activity. The phytochemical constituents from the root bark of C. volkensii had better analgesic properties than antimalarial properties, justifying the use of the plant root bark as a remedy for pain. Copyright © 2011 Elsevier B.V. All rights reserved.

Rosette-Disrupting Effect of an Anti-Plasmodial Compound for the Potential Treatment of Plasmodium falciparum Malaria Complications

PubMed Central

Ch’ng, Jun-Hong; Moll, Kirsten; Quintana, Maria del Pilar; Chan, Sherwin Chun Leung; Masters, Ellen; Moles, Ernest; Liu, Jianping; Eriksson, Anders B.; Wahlgren, Mats

2016-01-01

The spread of artemisinin-resistant parasites could lead to higher incidence of patients with malaria complications. However, there are no current treatments that directly dislodge sequestered parasites from the microvasculature. We show that four common antiplasmodial drugs do not disperse rosettes (erythrocyte clusters formed by malaria parasites) and therefore develop a cell-based high-throughput assay to identify potential rosette-disrupting compounds. A pilot screen of 2693 compounds identified Malaria Box compound MMV006764 as a potential candidate. Although it reduced rosetting by a modest 20%, MMV006764 was validated to be similarly effective against both blood group O and A rosettes of three laboratory parasite lines. Coupled with its antiplasmodial activity and drug-likeness, MMV006764 represents the first small-molecule compound that disrupts rosetting and could potentially be used in a resource-limited setting to treat patients deteriorating rapidly from malaria complications. Such dual-action drugs that simultaneously restore microcirculation and reduce parasite load could significantly reduce malaria morbidity and mortality. PMID:27403804

Synthesis and antiplasmodial evaluation of novel (4-aminobutyloxy)quinolines.

PubMed

Vandekerckhove, Stéphanie; Müller, Christian; Vogt, Dieter; Lategan, Carmen; Smith, Peter J; Chibale, Kelly; De Kimpe, Norbert; D'hooghe, Matthias

2013-01-01

A variety of 5-, 6- and 8-(4-aminobutyloxy)quinolines as novel oxygen analogues of known 4- and 8-(4-aminobutylamino)quinoline antimalarial drugs was generated from hydroxyquinolines through a three-step approach with a rhodium-catalyzed hydroformylation as the key step. Antiplasmodial assays of these new quinolines revealed micromolar potency for all representatives against a chloroquine-sensitive strain of Plasmodium falciparum, and three compounds showed submicromolar activity against a chloroquine-resistant strain of P. falciparum with IC(50)-values ranging between 150 and 680 nM. Copyright © 2012 Elsevier Ltd. All rights reserved.

Study of the interaction of antiplasmodial strychnine derivatives with the glycine receptor.

PubMed

Philippe, Geneviève; Nguyen, Laurent; Angenot, Luc; Frédérich, Michel; Moonen, Gustave; Tits, Monique; Rigo, Jean-Michel

2006-01-13

Strychnos icaja Baill. (Loganiaceae) is a liana found in Central Africa known to be an arrow and ordeal poison but also used by traditional medicine to treat malaria. Recently, many dimeric or trimeric indolomonoterpenic alkaloids with antiplasmodial properties have been isolated from its rootbark. Since these alkaloids are derivatives of strychnine, it was important, in view of their potential use as antimalarial drugs, to assess their possible convulsant strychnine-like properties. In that regard, their interaction with the strychnine-sensitive glycine receptor was investigated by whole-cell patch-clamp recordings on glycine-gated currents in mouse spinal cord neurons in culture and by [(3)H]strychnine competition assays on membranes from adult rat spinal cord. These experiments were carried out on sungucine (leading compound of the chemical class) and on the antiplasmodial strychnogucine B (dimeric) and strychnohexamine (trimeric). In comparison with strychnine, all compounds interact with a very poor efficacy and only at concentrations >1 microM with both [(3)H]strychnine binding and glycine-gated currents. Furthermore, the effects of strychnine and protostrychnine, a monomeric alkaloid (without antiplasmodial activity) also isolated from S. icaja and differing from strychnine only by a cycle opening, were compared in the same way. The weak interaction of protostrychnine confirms the importance of the G cycle ring structure in strychnine for its binding to the glycine receptor and its antagonist properties.

Synthesis of isocryptolepine analogues and their structure-activity relationship studies as antiplasmodial and antiproliferative agents.

PubMed

Aroonkit, Pasuk; Thongsornkleeb, Charnsak; Tummatorn, Jumreang; Krajangsri, Suppachai; Mungthin, Mathirut; Ruchirawat, Somsak

2015-04-13

Novel isocryptolepine analogues have been conveniently synthesized and evaluated for antimalarial and antiproliferative activities. We have found 3-fluoro-8-bromo-isocryptolepine (1n) to have the highest activities against chloroquine-resistant K1, chloroquine-sensitive 3D7, and chloroquine- and mefloquine-resistant SKF58 and SRIV35 strains. Several fluorine-substituted analogues (1b, 1n, and 1q) also showed excellent selectivities while maintaining good to excellent activities against all four Plasmodium falciparum strains. Additionally, antiproliferative properties of isocryptolepine derivatives against HepG2, HuCCA-1, MOLT-3 and A549 cancer cell lines are reported for the first time in this study. 2-Chloroisocryptolepine (1c) and benzo-fused-2-chloroisocryptolepine (1i) showed significant bioactivities whereas several novel fluorinated compounds and 2-chloro-8-bromoisocryptolepine (1f) displayed excellent selectivities. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Study of the in vitro antiplasmodial, antileishmanial and antitrypanosomal activities of medicinal plants from Saudi Arabia.

PubMed

Al-Musayeib, Nawal M; Mothana, Ramzi A; Al-Massarani, Shaza; Matheeussen, An; Cos, Paul; Maes, Louis

2012-09-25

The present study investigated the in vitro antiprotozoal activity of sixteen selected medicinal plants. Plant materials were extracted with methanol and screened in vitro against erythrocytic schizonts of Plasmodium falciparum, intracellular amastigotes of Leishmania infantum and Trypanosoma cruzi and free trypomastigotes of T. brucei. Cytotoxic activity was determined against MRC-5 cells to assess selectivity. The criterion for activity was an IC₅₀ < 10 μg/mL (<5 μg/mL for T. brucei) and a selectivity index of ≥4. Antiplasmodial activity was found in the extracts of Prosopis juliflora and Punica granatum. Antileishmanial activity against L. infantum was demonstrated in Caralluma sinaica and Periploca aphylla. Amastigotes of T. cruzi were affected by the methanol extract of Albizia lebbeck pericarp, Caralluma sinaica, Periploca aphylla and Prosopius juliflora. Activity against T. brucei was obtained in Prosopis juliflora. Cytotoxicity (MRC-5 IC₅₀ < 10 μg/mL) and hence non-specific activities were observed for Conocarpus lancifolius.

Antimalarial and antiplasmodial activity of husk extract and fractions of Zea mays.

PubMed

Okokon, Jude E; Antia, Bassey S; Mohanakrishnan, Dinesh; Sahal, Dinkar

2017-12-01

Zea mays L. (Poacae) husk decoctions are traditionally used in the treatment of malaria by various tribes in Nigeria. To assess the antimalarial and antiplasmodial potentials of the husk extract and fractions on malaria parasites using in vivo and in vitro models. The ethanol husk extract and fractions (187-748 mg/kg, p.o.) of Zea mays were investigated for antimalarial activity against Plasmodium berghei using rodent (mice) malaria models and in vitro activity against chloroquine sensitive (Pf 3D7) and resistant (Pf INDO) strains of Plasmodium falciparum using the SRBR green assay method. Median lethal dose and cytotoxic activities against HeLa and HEKS cells were also carried out. The GCMS analysis of the most active fraction was carried out. The husk extract (187-748 mg/kg, p.o.) with LD 50 of 1874.83 mg/kg was found to exert significant (p < 0.05-0.001) antimalarial activity against P. berghei infection in suppressive, prophylactive and curative tests. The crude extract and fractions also exerted prominent activity against both chloroquine sensitive (Pf 3D7) and resistant (Pf INDO) strains of P. falciparum with the ethyl acetate fraction exerting the highest activity with IC 50 values of 9.31 ± 0.46 μg/mL (Pf 3D7) and 3.69 ± 0.66 μg/mL (Pf INDO). The crude extract and fractions were not cytotoxic to the two cell lines tested with IC 50 values of >100 μg/mL against both HeLa and HEKS cell lines. These results suggest that the husk extract/fractions of Zea mays possesses antimalarial and antiplasmodial activities and these justify its use in ethnomedicine to treat malaria infections.

In vitro antiplasmodial activity of plants used in Benin in traditional medicine to treat malaria.

PubMed

Bero, Joanne; Ganfon, Habib; Jonville, Marie-Caroline; Frédérich, Michel; Gbaguidi, Fernand; DeMol, Patrick; Moudachirou, Mansourou; Quetin-Leclercq, Joëlle

2009-04-21

The aim of the study was to evaluate the in vitro antiplasmodial activity of crude extracts of 12 plant species traditionally used in Benin for the treatment of malaria in order to validate their use. For each species, dichloromethane, methanol and total aqueous extracts were tested. The antiplasmodial activity of extracts was evaluated using the measurement of the plasmodial lactate dehydrogenase activity on chloroquine-sensitive (3D7) and resistant (W2) strains of Plasmodium falciparum. The selectivity of the different extracts was evaluated using the MTT test on J774 macrophage-like murine cells and WI38 human normal fibroblasts. The best growth inhibition of both strains of Plasmodium falciparum was observed with the dichloromethane extracts of Acanthospermum hispidum DC. (Asteraceae) (IC(50)=7.5 microg/ml on 3D7 and 4.8 microg/ml on W2), Keetia leucantha (K. Krause) Bridson (syn. Plectronia leucantha Krause) (Rubiaceae) leaves and twigs (IC(50)=13.8 and 11.3 microg/ml on 3D7 and IC(50)=26.5 and 15.8 microg/ml on W2, respectively), Carpolobia lutea G.Don. (Polygalaceae) (IC(50)=19.4 microg/ml on 3D7 and 8.1 microg/ml on W2) and Strychnos spinosa Lam. (Loganiaceae) leaves (IC(50)=15.6 microg/ml on 3D7 and 8.9 microg/ml on W2). All these extracts had a low cytotoxicity. Our study gives some justifications for the traditional uses of some investigated plants.

Antiplasmodial activity of plant extracts used in west African traditional medicine.

PubMed

Mustofa; Valentin, A; Benoit-Vical, F; Pélissier, Y; Koné-Bamba, D; Mallié, M

2000-11-01

Five plants originating from Ivory Coast were selected after an ethnobotanical survey, Alchornea cordifolia, Mitragyna inermis, Nauclea diderrichii, Pterocarpus santalinoides, and Terminalia glaucescens. Traditional healers for the treatment of malaria commonly used these plants. Extracts of these plants were tested on three strains of Plasmodium falciparum, FcB1-Colombia and FcM29-Cameroon (chloroquine-resistant strains) and a Nigerian chloroquine-sensitive strain. Extracts were obtained by preparing decoction in water of the powdered plant, the technique used by most of the traditional healers. A radioactive micromethod allowed the evaluation of the in vitro activity of the extracts on P. falciparum. Concentrations inhibiting 50% of the parasite growth (IC(50)) ranged from 2.34 to more than 500 microg/ml according to the plant. For the most active plants (A. cordifolia and T. glaucescens) ethanol and pentane extracts were made and tested. The IC(50) values obtained for these extracts ranged from 0.35 to 43.40 microg/ml. The stage specificity of the ethanol extracts of A. cordifolia and T. glaucescens and pentane extract of T. glaucescens on the parasite erythrocytic cycle were determined. The ethanol extract of T. glaucescens showed its highest activity at the transition from the trophozoite to the schizont stages. Cytotoxicity was estimated on human fibroblasts (HeLa) cells and a cytotoxicity/antiplasmodial index was calculated, it ranged between 5 and 21, and the best antiplasmodial extract (T. glaucescens ethanol extract) had the higher index (>20).

Antiplasmodial agents from the Bhutanese medicinal plant Corydalis calliantha.

PubMed

Wangchuk, Phurpa; Bremner, John B; Rattanajak, Roonglawan; Kamchonwongpaisan, Sumalee

2010-04-01

The alkaloidal components of the Bhutanese medicinal plant Corydalis calliantha Long, which is used for the treatment of malaria, have been assessed. Four known alkaloids, protopine (1), scoulerine (2), cheilanthifoline (3) and stylopine (4) are reported from this plant for the first time. The protopine alkaloid, protopine, and the tetrahydroprotoberine alkaloid, cheilanthifoline, showed promising in vitro antiplasmodial activities against Plasmodium falciparum, both wild type (TM4) and multidrug resistant (K1) strains with IC(50) values in the range of 2.78-4.29 microM. Such activity had not been demonstrated previously for cheilanthifoline. The results thus support, at a molecular level, the clinical use of this plant in the Bhutanese traditional medicine and identified cheilanthifoline as a potential new antimalarial drug lead. Copyright (c) 2009 John Wiley & Sons, Ltd.

Synthesis and antimalarial testing of neocryptolepine analogues: addition of ester function in SAR study of 2,11-disubstituted indolo[2,3-b]quinolines.

PubMed

Lu, Wen-Jie; Wicht, Kathryn J; Wang, Li; Imai, Kento; Mei, Zhen-Wu; Kaiser, Marcel; El Sayed, Ibrahim El Tantawy; Egan, Timothy J; Inokuchi, Tsutomu

2013-06-01

This report describes the synthesis, and in vitro and in vivo antimalarial evaluations of certain ester-modified neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline) derivatives. The modifications were carried out by introducing ester groups at the C2 and/or C9 position on the neocryptolepine core and the terminal amino group of the 3-aminopropylamine substituents at the C11 position with a urea/thiourea unit. The antiplasmodial activities of our derivative agents against two different strains (CQS: NF54, and CQR: K1) and the cytotoxic activity against normal L6 cells were evaluated. The test results showed that the ester modified neocryptolepine derivatives have higher antiplasmodial activities against both strains and a low cytotoxic activity against normal cells. The best results were achieved by compounds 9c and 12b against the NF54 strain with the IC50/SI value as 2.27 nM/361 and 1.81 nM/321, respectively. While against K1 strain, all the tested compounds showed higher activity than the well-known antimalarial drug chloroquine. Furthermore, the compounds were tested for β-haematin inhibition and 12 were found to be more active than chloroquine (IC50 = 18 μM). Structure activity relationship studies exposed an interesting linear correlation between polar surface area of the molecule and β-haematin inhibition for this series. In vivo testing of compounds 7 and 8a against NF54 strain on Plasmodium berghei female mice showed that the introduction of the ester group increased the antiplasmodial activity of the neocryptolepine core substantially. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Mosquitocidal and antiplasmodial activity of Senna occidentalis (Cassiae) and Ocimum basilicum (Lamiaceae) from Maruthamalai hills against Anopheles stephensi and Plasmodium falciparum.

PubMed

Murugan, Kadarkarai; Aarthi, Narayanan; Kovendan, Kalimuthu; Panneerselvam, Chellasamy; Chandramohan, Balamurugan; Kumar, Palanisamy Mahesh; Amerasan, Duraisamy; Paulpandi, Manickam; Chandirasekar, Ramachandran; Dinesh, Devakumar; Suresh, Udaiyan; Subramaniam, Jayapal; Higuchi, Akon; Alarfaj, Abdullah A; Nicoletti, Marcello; Mehlhorn, Heinz; Benelli, Giovanni

2015-10-01

Each year, mosquito-borne diseases infect nearly 700 million people, resulting to more than 1 million deaths. In this study, we evaluated the larvicidal, pupicidal, and smoke toxicity of Senna occidentalis and Ocimum basilicum leaf extracts against the malaria vector Anopheles stephensi. Furthermore, the antiplasmodial activity of plant extracts was evaluated against chloroquine (CQ)-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. In larvicidal and pupicidal experiments, S. occidentalis LC50 ranged from 31.05 (I instar larvae) to 75.15 ppm (pupae), and O. basilicum LC50 ranged from 29.69 (I instar larvae) to 69 ppm (pupae). Smoke toxicity experiments conducted against adults showed that S. occidentalis and O. basilicum coils evoked mortality rates comparable to the pyrethrin-based positive control (38, 52, and 42%, respectively). In antiplasmodial assays, Senna occidentalis 50% inhibitory concentration (IC50) were 48.80 μg/ml (CQ-s) and 54.28 μg/ml (CQ-r), while O. basilicum IC50 were 68.14 μg/ml (CQ-s) and 67.27 μg/ml (CQ-r). Overall, these botanicals could be considered as potential sources of metabolites to build newer and safer malaria control tools.

Novel oxazine skeletons as potential antiplasmodial active ingredients: Synthesis, in vitro and in vivo biology of some oxazine entities produced via cyclization of novel chalcone intermediates.

PubMed

Tiwari, Vandana; Meshram, Jyotsna; Ali, Parvez; Sheikh, Javed; Tripathi, Umanath

2011-08-01

A novel series of 6-(2-chloroquinolin-3-yl)-4-substituted-phenyl-6H-1,3-oxazin-2-amines were synthesized and evaluated for in vitro antimalarial efficacy against chloroquine sensitive (MRC-02) as well as chloroquine resistant (RKL9) strains of Plasmodium falciparum. The activity tested was at nanomolar concentration. β-Hematin formation inhibition activity (BHIA(50)) of oxazines were determined and correlated with antimalarial activity. A reasonably good correlation (r = 0.49 and 0.51, respectively) was observed between antimalarial activity (IC(50)) and BHIA(50). This suggests that antimalarial mode of action of these compounds seems to be similar to that of chloroquine and involves the inhibition of hemozoin formation. Some of the compounds were showing better antimalarial activity than chloroquine against resistant strain of P. falciparum and were also found to be active in the in vivo experiment.

In vitro and in vivo anti-malarial activity of plants from the Brazilian Amazon.

PubMed

Lima, Renata B S; Rocha e Silva, Luiz F; Melo, Marcia R S; Costa, Jaqueline S; Picanço, Neila S; Lima, Emerson S; Vasconcellos, Marne C; Boleti, Ana Paula A; Santos, Jakeline M P; Amorim, Rodrigo C N; Chaves, Francisco C M; Coutinho, Julia P; Tadei, Wanderli P; Krettli, Antoniana U; Pohlit, Adrian M

2015-12-18

The anti-malarials quinine and artemisinin were isolated from traditionally used plants (Cinchona spp. and Artemisia annua, respectively). The synthetic quinoline anti-malarials (e.g. chloroquine) and semi-synthetic artemisinin derivatives (e.g. artesunate) were developed based on these natural products. Malaria is endemic to the Amazon region where Plasmodium falciparum and Plasmodium vivax drug-resistance is of concern. There is an urgent need for new anti-malarials. Traditionally used Amazonian plants may provide new treatments for drug-resistant P. vivax and P. falciparum. Herein, the in vitro and in vivo antiplasmodial activity and cytotoxicity of medicinal plant extracts were investigated. Sixty-nine extracts from 11 plant species were prepared and screened for in vitro activity against P. falciparum K1 strain and for cytotoxicity against human fibroblasts and two melanoma cell lines. Median inhibitory concentrations (IC50) were established against chloroquine-resistant P. falciparum W2 clone using monoclonal anti-HRPII (histidine-rich protein II) antibodies in an enzyme-linked immunosorbent assay. Extracts were evaluated for toxicity against murine macrophages (IC50) and selectivity indices (SI) were determined. Three extracts were also evaluated orally in Plasmodium berghei-infected mice. High in vitro antiplasmodial activity (IC50 = 6.4-9.9 µg/mL) was observed for Andropogon leucostachyus aerial part methanol extracts, Croton cajucara red variety leaf chloroform extracts, Miconia nervosa leaf methanol extracts, and Xylopia amazonica leaf chloroform and branch ethanol extracts. Paullinia cupana branch chloroform extracts and Croton cajucara red variety leaf ethanol extracts were toxic to fibroblasts and or melanoma cells. Xylopia amazonica branch ethanol extracts and Zanthoxylum djalma-batistae branch chloroform extracts were toxic to macrophages (IC50 = 6.9 and 24.7 µg/mL, respectively). Andropogon leucostachyus extracts were the most selective (SI >28.2) and the most active in vivo (at doses of 250 mg/kg, 71% suppression of P. berghei parasitaemia versus untreated controls). Ethnobotanical or ethnopharmacological reports describe the anti-malarial use of these plants or the antiplasmodial activity of congeneric species. No antiplasmodial activity has been demonstrated previously for the extracts of these plants. Seven plants exhibit in vivo and or in vitro anti-malarial potential. Future work should aim to discover the anti-malarial substances present.

Antimalarial evaluation of selected medicinal plant extracts used in Iranian traditional medicine

PubMed Central

Haddad, Mohammad Hossein Feiz; Mahbodfar, Hamidreza; Zamani, Zahra; Ramazani, Ali

2017-01-01

Objective(s): In an attempt to discover new natural active extracts against malaria parasites, the present study evaluated the antiplasmodial properties of selected plants based on Iranian traditional medicine. Materials and Methods: Ten plant species found in Iran were selected and collected based on the available literature about the Iranian traditional medicine. The methanolic extracts of these plants were investigated for in vitro antimalarial properties against chloroquine-sensitive (3D7) and multi-drug resistant (K1) strains of Plasmodium falciparum. Their in vivo activity against Plasmodium berghei infection in mice was also determined. Cytotoxicity tests were carried out using the Raji cells line using the MTT assay. The extracts were phytochemically screened for their active constituents. Results: According to the IC50 and selectivity index (SI) values, of the 10 selected plant species, Citrullus colocynthis, Physalis alkekengi, and Solanum nigrum displayed potent in vitro antimalarial activity against both 3D7 and K1 strains with no toxicity (IC50= 2.01-18.67 µg/ml and SI=3.55 to 19.25). Comparisons between treated and untreated control mice showed that the mentioned plant species reduced parasitemia by 65.08%, 57.97%, and 60.68%, respectively. The existence of antiplasmodial compounds was detected in these plant extracts. Conclusion: This was the first study to highlight the in vitro and in vivo antiplasmodial effects of C. colocynthis, P. alkekengi, and S. nigrum in Iran. Future studies can use these findings to design further biological tests to identify the active constituents of the mentioned plant species and clarify their mechanism of action. PMID:28804611

Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues

PubMed Central

Tjhin, Erick T.; Siddiqui, Ghizal; Marquez, Rodolfo; Saliba, Kevin J.

2018-01-01

The malaria-causing blood stage of Plasmodium falciparum requires extracellular pantothenate for proliferation. The parasite converts pantothenate into coenzyme A (CoA) via five enzymes, the first being a pantothenate kinase (PfPanK). Multiple antiplasmodial pantothenate analogues, including pantothenol and CJ-15,801, kill the parasite by targeting CoA biosynthesis/utilisation. Their mechanism of action, however, remains unknown. Here, we show that parasites pressured with pantothenol or CJ-15,801 become resistant to these analogues. Whole-genome sequencing revealed mutations in one of two putative PanK genes (Pfpank1) in each resistant line. These mutations significantly alter PfPanK activity, with two conferring a fitness cost, consistent with Pfpank1 coding for a functional PanK that is essential for normal growth. The mutants exhibit a different sensitivity profile to recently-described, potent, antiplasmodial pantothenate analogues, with one line being hypersensitive. We provide evidence consistent with different pantothenate analogue classes having different mechanisms of action: some inhibit CoA biosynthesis while others inhibit CoA-utilising enzymes. PMID:29614109

Anti-Plasmodial Activity of Aroylhydrazone and Thiosemicarbazone Iron Chelators: Effect on Erythrocyte Membrane Integrity, Parasite Development and the Intracellular Labile Iron Pool

PubMed Central

Walcourt, Asikiya; Kurantsin-Mills, Joseph; Kwagyan, John; Adenuga, Babafemi B.; Kalinowski, Danuta S.; Lovejoy, David B.; Lane, Darius J. R.; Richardson, Des R.

2013-01-01

Iron chelators inhibit the growth of the malaria parasite, Plasmodium falciparum, in culture and in animal and human studies. We previously reported the anti-plasmodial activity of the chelators, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), 2-hydroxy-1-naphthylaldehyde 4-methyl-3-thiosemicarbazone (N4mT), and 2-hydroxy-1-naphthylaldehyde 4-phenyl-3-thiosemicarbazone (N4pT). In fact, these ligands showed greater growth inhibition of chloroquine-sensitive (3D7) and chloroquine-resistant (7G8) strains of P. falciparum in culture compared to desferrioxamine (DFO). The present study examined the effects of 311, N4mT and N4pT on erythrocyte membrane integrity and asexual parasite development. While the characteristic biconcave disk shape of the erythrocytes was unaffected, the chelators caused very slight hemolysis at IC50 values that inhibited parasite growth. The chelators 311, N4mT and N4pT affected all stages of the intra-erythrocytic development cycle (IDC) of P. falciparum in culture. However, while these ligands primarily affected the ring-stage, DFO inhibited primarily trophozoite and schizont-stages. Ring, trophozoite and schizont-stages of the IDC were inhibited by significantly lower concentrations of 311, N4mT, and N4pT (IC50 = 4.45 ± 1.70, 10.30 ± 4.40, and 3.64 ± 2.00 μM, respectively) than DFO (IC50 = 23.43 ± 3.40 μM). Complexation of 311, N4mT and N4pT with iron reduced their anti-plasmodial activity. Estimation of the intracellular labile iron pool (LIP) in erythrocytes showed that the chelation efficacy of 311, N4mT and N4pT corresponded to their anti-plasmodial activity, suggesting that the LIP may be a potential source of non-heme iron for parasite metabolism within the erythrocyte. This study has implications for malaria chemotherapy that specifically disrupts parasite iron utilization. PMID:24028863

In vitro antiplasmodial activity and prophylactic potentials of extract and fractions of Trema orientalis (Linn.) stem bark.

PubMed

Olanlokun, John Oludele; David, Oluwole Moses; Afolayan, Anthony Jide

2017-08-15

Trema orientalis (T. orientalis Linn) has been used in the management of malaria in the western part of Nigeria and despite its application in ethnomedicine, there is dearth of scientific evidence to justify the acclaimed prophylactic antimalarial usage of the plant. The aim of this study is to assess the in vitro antiplasmodial cell-free assay and chemopreventive efficacy of the methanol extract of the stem bark of T. orientalis and its fractions as a prophylactic regimen for malaria prevention. Also, the antimicrobial activities of the extract and the fractions were investigated. Vacuum liquid chromatography was used to obtain dichloromethane, ethylacetate and methanol fractions from the methanol extract of T. orientalis. The fractions were tested for their prophylactic and cell-free antimalarial activity using murine models and β-hematin formation assay respectively. Disc diffusion method was used to determine the antibacterial activity of the extract and its fractions against both Gram-positive and Gram-negative bacteria. In the prophylactic experiment, dichloromethane (DCMF), methanol fraction (MF) and extract (ME) (in this order) showed significant chemopreventive effects against P. berghei invasion of the red blood cells when compared with both Sulfadoxine-Pyrimethamine (SP) and untreated controls. Results of the in vitro study showed that the DCMF had the highest effect in preventing the formation of β-hematin when compared with other fractions. The DCMF also had the highest percentage inhibition of β-hematin formation when compared with chloroquine. The extract and fractions showed a concentration dependent antibacterial activity. Methanol extract had a pronounced inhibitory effect on Enterobacter cloaca ATCC 13047 and Enterococcus faecalis ATCC 29212. Serratia mercescens ATCC 9986 and Pseudomonas aeruginosa ATCC 19582 were the most susceptible bacteria. The results obtained showed that both extract and fractions of T. orientalis possessed antiplasmodial and antimicrobial activity.

Biological and Phytochemical Investigations on Caesalpinia benthamiana, a Plant Traditionally Used as Antimalarial in Guinea

PubMed Central

Loua, Jean; Traore, Mohamed Sahar; Camara, Aissata; Balde, Mamadou Aliou; Maes, Louis; Pieters, Luc

2017-01-01

Caesalpinia benthamiana is widely used as antimalarial in Guinean traditional medicine. Leaf extracts of the plant were tested for their in vitro antiprotozoal activity against Trypanosoma brucei brucei and T. cruzi and the chloroquine-sensitive Ghana strain of Plasmodium falciparum along with their cytotoxicity on MRC-5 cells. The methanolic extract showed the strongest antiprotozoal activity against P. falciparum (IC50 4 μg/ml), a good activity against T. brucei (IC50 13 μg/ml), and a moderate activity against T. cruzi (IC50 31 μg/ml) along with an IC50 on human MRC-5 cells of 32 μg/ml. Bioassay-guided fractionation from the methanolic extract led to antiplasmodially active subfractions. A prospective, placebo-controlled ethnotherapeutic trial assessed the antimalarial effectiveness and tolerability of C. benthamiana syrup administered orally to children with uncomplicated malaria as compared with chloroquine syrup. Phytochemical screening of the leaf extracts indicated the presence of flavonoids, terpenoids, tannins, saponins, and iridoids. PMID:29081823

Antiplasmodial activity of Xanthium strumarium against Plasmodium berghei-infected BALB/c mice.

PubMed

Chandel, Sanjeev; Bagai, Upma; Vashishat, Nisha

2012-03-01

The present work was undertaken to evaluate the antiplasmodial activity of ethanolic leaves extract of traditional medicinal plant Xanthium strumarium in Plasmodium berghei-infected BALB/c mice along with phytochemical screening and acute toxicity test to support its traditional medicinal use as a malaria remedy. The ethanolic leaves extract of X. strumarium (ELEXS) 150, 250, 350 and 500 mg/kg/day demonstrated dose-dependent chemosuppression during early and established infection long with significant (p < 0.001) repository activity. The oral administration of 500 mg/kg/day concentration showed a maximum of 88.6% chemosuppression during early infection, which was more than that of the standard drug chloroquine (5 mg/kg/day) with 88.3% chemosuppression. However, 60% mortality has been found in this group. The LD(50) of ELEXS was found to be 1.5 g/kg/mouse. The administration of 350 mg/kg/day concentration of extract have been found to exert 90.40% chemosuppression during repository infection, which was well comparable to standard drug pyrimethamine (1.2 mg/kg/day) exerting 92.91% chemosuppression. The extract has been found to enhance mean survival time of mice from 21 to 26 days with 250 and 350 mg/kg/day concentrations, while 150 mg/kg/day concentration has been found to sustain all the mice up to 29 days which was similar to the employed standard drug chloroquine (5 mg/kg/day). All these findings support the ethanopharmacological use of X. strumarium as malarial remedy and indicate the potential of plant for active antiplasmodial components.

Incorporation of basic side chains into cryptolepine scaffold: structure-antimalarial activity relationships and mechanistic studies.

PubMed

Lavrado, João; Cabal, Ghislain G; Prudêncio, Miguel; Mota, Maria M; Gut, Jiri; Rosenthal, Philip J; Díaz, Cecília; Guedes, Rita C; dos Santos, Daniel J V A; Bichenkova, Elena; Douglas, Kenneth T; Moreira, Rui; Paulo, Alexandra

2011-02-10

The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and their evaluations for antiplasmodial and cytotoxicity properties are reported. Propyl, butyl, and cycloalkyl diamine side chains significantly increased activity against chloroquine-resistant Plasmodium falciparum strains while reducing cytotoxicity when compared with the parent compound. Localization studies inside parasite blood stages by fluorescence microscopy showed that these derivatives accumulate inside the nucleus, indicating that the incorporation of a basic side chain is not sufficient enough to promote selective accumulation in the acidic digestive vacuole of the parasite. Most of the compounds within this series showed the ability to bind to a double-stranded DNA duplex as well to monomeric hematin, suggesting that these are possible targets associated with the observed antimalarial activity. Overall, these novel cryptolepine analogues with substantially improved antiplasmodial activity and selectivity index provide a promising starting point for development of potent and highly selective agents against drug-resistant malaria parasites.

Evaluation of antiplasmodial and antileishmanial activities of herbal medicine Pseudelephantopus spiralis (Less.) Cronquist and isolated hirsutinolide-type sesquiterpenoids.

PubMed

Girardi, Cynthia; Fabre, Nicolas; Paloque, Lucie; Ramadani, Arba Pramundita; Benoit-Vical, Françoise; González-Aspajo, German; Haddad, Mohamed; Rengifo, Elsa; Jullian, Valérie

2015-07-21

Pseudelephantopus spiralis (Less.) Cronquist is distributed in the Caribbean, Mesoamerica and Latin America. Preparations of the plant are traditionally used in Latin America for the treatment of various diseases including fever, malaria, and spleen or liver inflammations. Aerial parts of P. spiralis were extracted with either ethanol or distilled water. Seven hirsutinolide-type sesquiterpenoids were isolated: 8-acetyl-13-ethoxypiptocarphol (1), diacetylpiptocarphol (2), piptocarphins A (3), F (4) and D (5), (1S(*),4R(*),8S(*),10R(*))-1,4-epoxy-13-ethoxy-1,8,10-trihydroxygermacra-5E,7(11)-dien-6,12-olide (6), and piptocarphol (7). Extracts and isolated compounds (2, 3, 5-7) were screened for their in vitro antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum strain FcM29-Cameroon and antileishmanial activity against three stages of Leishmania infantum. Their cytotoxicities were also evaluated against healthy VERO cell lines and J774A.1 macrophages, the host cells of the Leishmania parasites in humans. Aqueous extracts showed a greater inhibitory effect than alcoholic extracts, with IC50 on P. falciparum of 3.0µg/mL versus 21.1µg/mL, and on L. infantum of 13.4µg/mL versus >50µg/mL. Both extracts were found to be cytotoxic to VERO cells (CC50<3µg/mL). Sesquiterpene lactones 2 and 3 showed the best activity against both parasites but failed in selectivity. Carbon 8 hydroxylated hirsutinolides 5-7 presented the particularity of exhibiting two conformers observed in solution during extensive NMR analyses in CD3OD and UHPLC-MS. The presence of a hydroxyl function at C-8 decreased the activity of 5-7 on the two parasites and also on VERO cells. The antiplasmodial activity displayed by the aqueous extract explains the traditional use of P. spiralis in the treatment of malaria. This activity seems to be attributable to the presence of sesquiterpene lactones 2 and 3, the most active against P. falciparum. Aqueous extract and compounds 2, 3 and 6 were also active against L. infantum but lacked in selectivity due to their cytotoxicity towards macrophages. Exploring the safety and antiplasmodial efficacy of this traditional remedy will require further toxicological and in vivo studies in the light of the cytotoxicity towards healthy cell lines displayed by the aqueous extract and compounds 2 and 3. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Diversity and biological activities of the bacterial community associated with the marine sponge Phorbas tenacior (Porifera, Demospongiae).

PubMed

Dupont, S; Carré-Mlouka, A; Descarrega, F; Ereskovsky, A; Longeon, A; Mouray, E; Florent, I; Bourguet-Kondracki, M L

2014-01-01

The diversity of the cultivable microbiota of the marine sponge Phorbas tenacior frequently found in the Mediterranean Sea was investigated, and its potential as a source of antimicrobial, antioxidant and antiplasmodial compounds was evaluated. The cultivable bacterial community was studied by isolation, cultivation and 16S rRNA gene sequencing. Twenty-three bacterial strains were isolated and identified in the Proteobacteria (α or γ classes) and Actinobacteria phyla. Furthermore, three different bacterial morphotypes localized extracellularly within the sponge tissues were revealed by microscopic observations. Bacterial strains were assigned to seven different genera, namely Vibrio, Photobacterium, Shewanella, Pseudomonas, Ruegeria, Pseudovibrio and Citricoccus. The strains affiliated to the same genus were differentiated according to their genetic dissimilarities using random amplified polymorphic DNA (RAPD) analyses. Eleven bacterial strains were selected for evaluation of their bioactivities. Three isolates Pseudovibrio P1Ma4, Vibrio P1MaNal1 and Citricoccus P1S7 revealed antimicrobial activity; Citricoccus P1S7 and Vibrio P1MaNal1 isolates also exhibited antiplasmodial activity, while two Vibrio isolates P1Ma8 and P1Ma5 displayed antioxidant activity. These data confirmed the importance of Proteobacteria and Actinobacteria associated with marine sponges as a reservoir of bioactive compounds. This study presents the first report on the diversity of the cultivable bacteria associated with the marine sponge Phorbas tenacior, frequently found in the Mediterranean Sea. Evaluation of the antiplasmodial, antimicrobial and antioxidant activities of the isolates has been investigated and allowed to select bacterial strains, confirming the importance of Proteobacteria and Actinobacteria as sources of bioactive compounds. © 2013 The Society for Applied Microbiology.

Antiplasmodial Activity and Toxicological Assessment of Curcumin PLGA-Encapsulated Nanoparticles

PubMed Central

Busari, Zulaikha A.; Dauda, Kabiru A.; Morenikeji, Olajumoke A.; Afolayan, Funmilayo; Oyeyemi, Oyetunde T.; Meena, Jairam; Sahu, Debasis; Panda, Amulya K.

2017-01-01

Curcumin is a polyphenolic pigment isolated from the rhizomes of Curcuma longa (turmeric), a medicinal plant widely used in the ancient Indian and Chinese medicine. The antiplasmodial activity of curcumin is often hampered by its fast metabolism and poor water solubility, thus its incorporation into a delivery system could circumvent this problem. This study aimed to evaluate the in vivo antiplasmodial activity and the toxicity assessment of curcumin incorporated into poly (lactic-co-glycolic) acid (PLGA) nanoparticles. Curcumin was loaded with poly (D,L-lactic-co-glycolic acid) (PLGA) using solvent evaporation from oil-in-water single emulsion method. The nanoparticles were characterized and evaluated in vivo for antimalarial activities using Peter’s 4-day suppressive protocol in mice model. Hematological and hepatic toxicity assays were performed on whole blood and plasma, respectively. In vivo anti-parasitic test and toxicity assays for free and encapsulated drug were performed at 5 and 10 mg/kg. In vitro cytotoxicity of free and PLGA encapsulated curcumin (Cur-PLGA) to RAW 264.7 cell line was also determined at varying concentrations (1000–7.8 μg/mL). The size and entrapment efficiency of the nanoparticulate drug formulated was 291.2 ± 82.1 nm and 21.8 ± 0.4 respectively. The percentage parasite suppression (56.8%) at 5 mg/kg was significantly higher than in free drug (40.5%) of similar concentration (p < 0.05) but not at 10 mg/kg (49.5%) at 4-day post-treatment. There were no significant differences in most of the recorded blood parameters in free curcumin and PLGA encapsulated nanoparticulate form (p > 0.05) except in lymphocytes which were significantly higher in Cur-PLGA compared to the free drug (p < 0.05). There were no significant differences in hepatotoxic biomarkers; aspartate aminotransferase and alanine aminotransferase concentrations in various treatment groups (p > 0.05). At higher concentrations (1000 and 500 μg/mL), Cur-PLGA entrapped nanoparticle showed higher toxicity compared with the free drug (p < 0.05) in exposed RAW 264.7 cell line. The cell viability was, however, higher in Cur-PLGA nanoparticles than in free curcumin at lower concentrations (p > 0.05). The antiplasmodial activity and safety of Cur-PLGA was better at lower concentration. PMID:28932197

Ganoboninketals A-C, Antiplasmodial 3,4-seco-27-Norlanostane Triterpenes from Ganoderma boninense Pat.

PubMed

Ma, Ke; Ren, Jinwei; Han, Junjie; Bao, Li; Li, Li; Yao, Yijian; Sun, Chen; Zhou, Bing; Liu, Hongwei

2014-08-22

Three new nortriterpenes, ganoboninketals A-C (1-3), featuring rearranged 3,4-seco-27-norlanostane skeletons and highly complex polycyclic systems were isolated from the medicinal mushroom Ganoderma boninense. The structures of the new metabolites were established by spectroscopic methods. The absolute configurations in 1-3 were assigned by electronic circular dichroism (ECD) calculations. Compounds 1-3 showed antiplasmodial activity against Plasmodium falciparum with IC50 values of 4.0, 7.9, and 1.7 μM, respectively. Compounds 1 and 3 also displayed weak cytotoxicity against A549 cell line with IC50 values of 47.6 and 35.8 μM, respectively. Compound 2 showed weak cytotoxicity toward HeLa cell line with an IC50 value of 65.5 μM. Compounds 1-3 also presented NO inhibitory activity in the LPS-induced macrophages with IC50 values of 98.3, 24.3, and 60.9 μM, respectively.

Antiplasmodial dimeric chalcone derivatives from the roots of Uvaria siamensis.

PubMed

Salae, Abdul-Wahab; Chairerk, Orapan; Sukkoet, Piyanut; Chairat, Therdsak; Prawat, Uma; Tuntiwachwuttikul, Pittaya; Chalermglin, Piya; Ruchirawat, Somsak

2017-03-01

Four dimeric chalcone derivatives, 8″,9″-dihydrowelwitschin H, uvarins A-C, a naphthalene derivative, 2-hydroxy-3-methoxy-6-(4'- hydroxyphenyl)naphthalene, and the known dimeric chalcones, dependensin and welwitschin E, flavonoids, a cyclohexane oxide derivative, an aromatic aldehyde were isolated from the roots of Uvaria siamensis (Annonaceae). The structures of the compounds were elucidated by spectroscopic analysis, as well as by comparison with literature data. The isolated compounds with a sufficient amount for biological assays were evaluated for their antimalarial, antimycobacterial, and cytotoxic activities. The dimeric chalcones 8″,9″-dihydrowelwitschin H, uvarins B and C, dependensin and welwitschin E showed strong antiplasmodial activity with IC 50 values of 3.10, 3.02, 3.09, 4.21 and 3.99 μg/mL, respectively. A possible biosynthesis pathway of the dimeric chalcones is discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Wayanin and guaijaverin, two active metabolites found in a Psidium acutangulum Mart. ex DC (syn. P. persoonii McVaugh) (Myrtaceae) antimalarial decoction from the Wayana Amerindians.

PubMed

Houël, Emeline; Nardella, Flore; Jullian, Valérie; Valentin, Alexis; Vonthron-Sénécheau, Catherine; Villa, Pascal; Obrecht, Adeline; Kaiser, Marcel; Bourreau, Eliane; Odonne, Guillaume; Fleury, Marie; Bourdy, Geneviève; Eparvier, Véronique; Deharo, Eric; Stien, Didier

2016-07-01

Psidium acutangulum Mart. ex DC is a small tree used by the Wayana Amerindians from the Upper-Maroni in French Guiana for the treatment of malaria. In a previous study, we highlighted the in vitro antiplasmodial, antioxidant and anti-inflammatory potential of the traditional decoction of P. acutangulum aerial parts. Our goal was then to investigate on the origin of the biological activity of the traditional remedy, and eventually characterize active constituents. Liquid-liquid extractions were performed on the decoction, and the antiplasmodial activity evaluated against chloroquine-resistant FcB1 ([(3)H]-hypoxanthine bioassay) and 7G8 (pLDH bioassay) P. falciparum strains, and on a chloroquine sensitive NF54 ([(3)H]-hypoxanthine bioassay) P. falciparum strain. The ethyl acetate fraction (D) was active and underwent bioguided fractionation. All the isolated compounds were tested on P. falciparum FcB1 strain. In vitro anti-inflammatory activity (IL-1β, IL-6, IL-8, TNFα) of the ethyl acetate fraction and of an anti-Plasmodium active compound, was concurrently assessed on LPS-stimulated human PBMC and NO secretion inhibition was measured on LPS stimulated RAW murine macrophages. Cytotoxicity of the fractions and pure compounds was measured on VERO cells, L6 mammalian cells, PBMCs, and RAW cells. Fractionation of the ethyl acetate soluble fraction (IC50 ranging from 3.4 to <1µg/mL depending on the parasite strain) led to the isolation of six pure compounds: catechin and five glycosylated quercetin derivatives. These compounds have never been isolated from this plant species. Two of these compounds (wayanin and guaijaverin) were found to be moderately active against P. falciparum FcB1 in vitro (IC50 5.5 and 6.9µM respectively). We proposed the name wayanin during public meetings organized in June 2015 in the Upper-Maroni villages, in homage to the medicinal knowledge of the Wayana population. At 50µg/mL, the ethyl acetate fraction (D) significantly inhibited IL-1β secretion (-46%) and NO production (-21%), as previously observed for the decoction. The effects of D and guiajaverin (4) on the secretion of other cytokines or NO production were not significant. The confirmed antiplasmodial activity of the ethyl acetate soluble fraction of the decoction and of the isolated compounds support the previous results obtained on the P. acutangulum decoction. The antiplasmodial activity might be due to a mixture of moderately active non-toxic flavonoids. The anti-inflammatory activities were less marked for ethyl acetate fraction (D) than for the decoction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In vivo and in vitro antiplasmodial activities of some plants traditionally used in Guatemala against malaria.

PubMed Central

Franssen, F F; Smeijsters, L J; Berger, I; Medinilla Aldana, B E

1997-01-01

We present an evaluation of the antiplasmodial and cytotoxic effects of four plants commonly used in Guatemalan folk medicine against malaria. Methanol extracts of Simarouba glauca D. C., Sansevieria guineensis Willd, Croton guatemalensis Lotsy, and Neurolaena lobata (L.)R.Br. significantly reduced parasitemias in Plasmodium berghei-infected mice. Dichloromethane fractions were screened for their cytotoxicities on Artemia salina (brine shrimp) larvae, and 50% inhibitory concentrations were determined for Plasmodium falciparum in in vitro cultures. Both chloroquine-susceptible and -resistant strains of P. falciparum were significantly inhibited by these extracts. Of all dichloromethane extracts, only the S. glauca cortex extract was considered to be toxic to nauplii of A. salina in the brine shrimp test. PMID:9210673

In vivo and in vitro antiplasmodial activities of some plants traditionally used in Guatemala against malaria.

PubMed

Franssen, F F; Smeijsters, L J; Berger, I; Medinilla Aldana, B E

1997-07-01

We present an evaluation of the antiplasmodial and cytotoxic effects of four plants commonly used in Guatemalan folk medicine against malaria. Methanol extracts of Simarouba glauca D. C., Sansevieria guineensis Willd, Croton guatemalensis Lotsy, and Neurolaena lobata (L.)R.Br. significantly reduced parasitemias in Plasmodium berghei-infected mice. Dichloromethane fractions were screened for their cytotoxicities on Artemia salina (brine shrimp) larvae, and 50% inhibitory concentrations were determined for Plasmodium falciparum in in vitro cultures. Both chloroquine-susceptible and -resistant strains of P. falciparum were significantly inhibited by these extracts. Of all dichloromethane extracts, only the S. glauca cortex extract was considered to be toxic to nauplii of A. salina in the brine shrimp test.

Antioxidant, antimalarial and antimicrobial activities of tannin-rich fractions, ellagitannins and phenolic acids from Punica granatum L.

PubMed

Reddy, Muntha K; Gupta, Sashi K; Jacob, Melissa R; Khan, Shabana I; Ferreira, Daneel

2007-05-01

The Punica granatum L. (pomegranate) by-product POMx was partitioned between water, EtOAc and n-BuOH, and the EtOAc and n-BuOH extracts were purified by XAD-16 and Sephadex LH-20 column chromatography to afford ellagic acid (1), gallagic acid (2), punicalins (3), and punicalagins (4). Compounds 1 - 4 and the mixture of tannin fractions (XAD-16 eluates) were evaluated for antioxidant, antiplasmodial, and antimicrobial activities in cell-based assays. The mixture of tannins (TPT), XAD-EtOAc, XAD-H2O, XAD-PJ and XAD-BuOH, exhibited IC50 values against reactive oxygen species (ROS) generation at 0.8 - 19 microg/mL. Compounds 1 - 4 showed IC50 values of 1.1, 3.2, 2.3 and 1.4 microM, respectively, against ROS generation and no toxicity up to 31.25 microg/mL against HL-60 cells. Gallagic acid (2) and punicalagins (4) exhibited antiplasmodial activity against Plasmodium falciparum D6 and W2 clones with IC50 values of 10.9, 10.6, 7.5 and 8.8 microM, respectively. Fractions XAD-EtOAc, XAD-BuOH, XAD-H2O and XAD-PJ compounds 1 - 4 revealed antimicrobial activity when assayed against Escherichia coli, Pseudomonas aeruginosa, Candida albicans, Cryptococcus neoformans, methicillin-resistant Staphylococcus aureus (MRSA), Aspergillus fumigatus and Mycobacterium intracellulare. Compounds 2 and 4 showed activity against P. aeruginosa, C. neoformans, and MRSA. This is the first report on the antioxidant, antiplasmodial and antimicrobial activities of POMx isolates, including structure-activity relationships (SAR) of the free radical inhibition activity of compounds 1 - 4. Our results suggest a beneficial effect from the daily intake of POMx and pomegranate juice (PJ) as dietary supplements to augment the human immune system's antioxidant, antimalarial and antimicrobial capacities.

Synthesized of 2,7 dihydroxyxanthone from xanthone and antimalarial activities

NASA Astrophysics Data System (ADS)

Amanatie; Jumina; Mustofa; Hanafi

2018-03-01

The purpose of the research is to synthesize 2,7-di-hydroxyxanthone compounds from xanthone and to evaluate antiplasmodial against activities. The synthesize of 2,7-di-hydroxyxanthone compounds worked with chromatogramphy methods including Thin Layer Chromatography (TLC), Vacuum Liquid Chromatography (VLC). A compound structures were determined based on the spectroscopic evidences including, Infrared (IR), one dimension (1-D) and two dimension (2-D) Nuclear Magnetic Resonance (NMR) spectra and comparison the spectroscopy data with related data from references. The biological properties of compounds are evaluated towards antiplasmodial against activity. The result of the product was obtained as white solid in 63.49% yield. The IR spectrum showed the absorption at 3433 cm-1 Which was reinforced with a sharp attack at 1087cm-1 indicating the stretching of OH, while the stretching of aromatic C=C appeared at 1620 cm-1. The 1H-NMR (500MHz, and DMSO –d6) spectrum showed that the aryl protons appeared in the region of δ12.98 ppm. In this region, there were 2 singlet at δH 12.98 ppm (1H, 2-OH) and (1H,7-OH) and shows the presence of two OH groups. Based on spectroscopy analyses, it could be started that the reaction of 2.7 di-aminoxanthone with NaNO2/HCl and H3PO4 produced 2.7-di-hydroxyxanthone. In vitro antiplasmodial assay of the product synthesized 2,7 di-hydroxyxanthones against. Falciparum strain of 3D7 showed that the IC50 values of 2,7-di-hydroxy xanthone, were 0.31 μg/mL, respectively.

Antiplasmodial activity of two medicinal plants against clinical isolates of Plasmodium falciparum and Plasmodium berghei infected mice.

PubMed

Attemene, Serge David Dago; Beourou, Sylvain; Tuo, Karim; Gnondjui, Albert Alloh; Konate, Abibatou; Toure, Andre Offianan; Kati-Coulibaly, Seraphin; Djaman, Joseph Alico

2018-03-01

Malaria is an infectious and deadly parasitic disease, associated with fever, anaemia and other ailments. Unfortunately the upsurge of plasmodium multidrug resistant constrained researchers to look for new effective drugs. Medicinal plants seem to be an unquenchable source of bioactive principles in the treatment of various diseases. The aim of this study was to assess the antiplasmodial activity of two Ivorian medicinal plants. The in vitro activity was evaluated against clinical isolates and Plasmodium falciparum K1 multidrug resistant strain using the fluorescence based SYBR green I assay. The in vivo bioassay was carried out using the classical 4 day suppressive and curative tests on Plasmodium berghei infected mice. Results showed that the in vitro bioassay of both plant extracts were found to exhibit a promising and moderate antiparasitic effects on clinical isolates (5 µg/mL < IC 50  < 15 µg/mL) and Plasmodium falciparum multidrug resistant K1 strain (15 µg/mL < IC 50  < 50 µg/mL). Furthermore, the in vivo antiplasmodial screening of both extracts showed a significant decrease in parasitemia, which was dose-dependent. Body temperature in mice treated with both extracts at experimental doses increased, compared to the negative control group and was dose-dependent. As for mice body weight a significant decrease ( p  < 0.001) was noticed in the negative control group compared to tested groups of animals. The hydroethanolic stem bark extract of Anthocleista djalonensis A Chev and leaves extract of Ziziphus mauritiana Lam exhibited anti-malarial activities. Therefore, the bioactive compounds of both plant extracts need to be investigated.

In Vitro Antiplasmodial Activities and Synergistic Combinations of Differential Solvent Extracts of the Polyherbal Product, Nefang

PubMed Central

Arrey Tarkang, Protus; Franzoi, Kathrin Diehl; Lee, Eunyoung; Freitas-Junior, Lucio; Liuzzi, Michel; Nolé, Tsabang; Ayong, Lawrence S.; Agbor, Gabriel A.; Okalebo, Faith A.; Guantai, Anastasia N.

2014-01-01

Nefang, a polyherbal product composed of Mangifera indica (bark and leaf), Psidium guajava, Carica papaya, Cymbopogon citratus, Citrus sinensis, and Ocimum gratissimum (leaves), is a potential therapy against P. falciparum malaria. In vitro antiplasmodial activities of its constituent solvent extracts were analyzed on CQ-sensitive (3D7) and multidrug resistant (Dd2) P. falciparum strains. The interactions involving the differential solvent extracts were further analyzed using a variable potency ratio drug combination approach. Effective concentration 50 (EC50) values were determined by nonlinear regression curve-fitting of the dose-response data and used in calculating the fractional inhibitory concentration 50 (FIC50) and combination indices (CI) for each pair. The derived EC50 values (3D7/Dd2, μg/mL) are Nefang-96.96/55.08, MiB-65.33/34.58, MiL-82.56/40.04, Pg-47.02/25.79, Cp-1188/317.5, Cc-723.3/141, Cs-184.4/105.1, and Og-778.5/118.9. Synergism was obtained with MiB/Pg (CI = 0.351), MiL/Pg (0.358), MiB/Cs (0.366), MiL/Cs (0.482), Pg/Cs (0.483), and Cs/Og (0.414) when analyzed at equipotency ratios. Cytotoxicity testing of Nefang and the solvent extracts on two human cell lines (Hep G2 and U2OS) revealed no significant toxicity relative to their antiplasmodial activities (SI > 20). Taken together, our data confirm the antimalarial activities of Nefang and its constituent plant extracts and identified extract pairs with promising synergistic interactions for exploitation towards a rational phytotherapeutic and evidence-based antimalarial drug discovery. PMID:24877138

The antiplasmodial activity of norcantharidin analogs

USDA-ARS?s Scientific Manuscript database

Despite the availability of many antimalarial drugs, including chloroquine (CQ), artemisinin, atovaquone, proguanil and sulphadoxine-pyrimethamine (SP), malaria remains a serious disease. Malaria is especially dangerous due to the ability of Plasmodium falciparum to evolve resistance to the most com...

Antiplasmodial activities of dyes against Plasmodium falciparum asexual and sexual stages: Contrasted uptakes of triarylmethanes Brilliant green, Green S (E142), and Patent Blue V (E131) by erythrocytes.

PubMed

Leba, Louis-Jérôme; Popovici, Jean; Estevez, Yannick; Pelleau, Stéphane; Legrand, Eric; Musset, Lise; Duplais, Christophe

2017-12-01

The search for safe antimalarial compounds acting against asexual symptom-responsible stages and sexual transmission-responsible forms of Plasmodium species is one of the major challenges in malaria elimination programs. So far, among current drugs approved for human use, only primaquine has transmission-blocking activity. The discovery of small molecules targeting different Plasmodium falciparum life stages remains a priority in antimalarial drug research. In this context, several independent studies have recently reported antiplasmodial and transmission-blocking activities of commonly used stains, dyes and fluorescent probes against P. falciparum including chloroquine-resistant isolates. Herein we have studied the antimalarial activities of dyes with different scaffold and we report that the triarylmethane dye (TRAM) Brilliant green inhibits the growth of asexual stages (IC 50  ≤ 2 μM) and has exflagellation-blocking activity (IC 50  ≤ 800 nM) against P. falciparum reference strains (3D7, 7G8) and chloroquine-resistant clinical isolate (Q206). In a second step we have investigated the antiplasmodial activities of two polysulfonated triarylmethane food dyes. Green S (E142) is weakly active against P. falciparum asexual stage (IC 50 ≃ 17 μM) whereas Patent Blue V (E131) is inactive in both antimalarial assays. By applying liquid chromatography techniques for the culture supernatant analysis after cell washings and lysis, we report the detection of Brilliant green in erythrocytes, the selective uptake of Green S (E142) by infected erythrocytes, whereas Patent Blue V (E131) could not be detected within non-infected and 3D7-infected erythrocytes. Overall, our results suggest that two polysulfonated food dyes might display different affinity with transporters or channels on infected RBC membrane. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Plants used by native Amazonian groups from the Nanay River (Peru) for the treatment of malaria.

PubMed

Ruiz, Lastenia; Ruiz, Liliana; Maco, Martha; Cobos, Marianela; Gutierrez-Choquevilca, Andréa-Luz; Roumy, Vincent

2011-01-27

In order to evaluate the antimalarial potential of traditional remedies used in Peru, Indigenous and Mestizo populations from the river Nanay in Loreto were interviewed about traditional medication for the treatment of malaria. The survey took place on six villages and led to the collection of 59 plants. 35 hydro-alcoholic extractions were performed on the 21 most cited plants. The extracts were then tested for antiplasmodial activity in vitro on Plasmodium falciparum chloroquine resistant strain (FCR-3), and ferriprotoporphyrin inhibition test was also performed in order to assume pharmacological properties. Extracts from 9 plants on twenty-one tested (Abuta rufescens, Ayapana lanceolata, Capsiandra angustifolia, Citrus limon, Citrus paradise, Minquartia guianensis, Potalia resinífera, Scoparia dulcis, and Physalis angulata) displayed an interesting antiplasmodial activity (IC(50)<10 μg/ml) and 16 remedies were active on the ferriprotoporphyrin inhibition test. The results give scientific validation to the traditional medical knowledge of the Amerindian and Mestizo populations from Loreto and exhibit a source of potentially active plants. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Seeds of Peganum Harmala L. chemical analysis, antimalarial and antioxidant activities, and cytotoxicity against human breast cancer cells.

PubMed

Chabir, Naziha; Ibrahim, Hany; Romdhane, Hany; Valentin, Alexis; Moukarzel, Beatrice; Mars, Mohamed; Bouajila, Jalloul

2014-01-01

The present study evaluated the levels of total phenolics, flavonoids, tannins and anthocyanins from Peganum harmala L. seeds and determined their antioxidant, antiplasmodial and anticancer potentials. Antioxidant activity was determined by DPPH and ABTS assays. Extracts of P. harmala seeds from Oudref and Djerba (two places in Tunisia) were obtained by successive extraction solvents: petroleum ether, chloroform, ethyl acetate, ethanol and water. Their composition was evaluated for phenolics (gallic acid equivalent 2.48 to 72.52 g/kg), tannins (catechin equivalent 0 to 25.27 g/kg), anthocyanins (cyanidin equivalent 0 to 20.56 mg/kg) and flavonoids (quercetin equivalent 0 to 3.12 g/kg). Ethanolic extract exerted the highest activities against a chloroquine-resistant strain of Plasmodium falciparum (IC₅₀=23 mg/L), against human breast cancer cells MCF7 (IC₅₀=32 mg/L) and against free radical (IC₅₀=19.09±3.07 mg/L). Correlations were studied between each chemical family and the three activities. Total phenolics content exhibited the highest correlation with antiplasmodial activity (R²=0.92) and with anticancer activity (R²=0.86), respectively.

Antimalarial Activity of Plant Metabolites.

PubMed

Pan, Wen-Hui; Xu, Xin-Ya; Shi, Ni; Tsang, Siu Wai; Zhang, Hong-Jie

2018-05-06

Malaria, as a major global health problem, continues to affect a large number of people each year, especially those in developing countries. Effective drug discovery is still one of the main efforts to control malaria. As natural products are still considered as a key source for discovery and development of therapeutic agents, we have evaluated more than 2000 plant extracts against Plasmodium falciparum . As a result, we discovered dozens of plant leads that displayed antimalarial activity. Our phytochemical study of some of these plant extracts led to the identification of several potent antimalarial compounds. The prior comprehensive review article entitled “Antimalarial activity of plant metabolites” by Schwikkard and Van Heerden (2002) reported structures of plant-derived compounds with antiplasmodial activity and covered literature up to the year 2000. As a continuation of this effort, the present review covers the antimalarial compounds isolated from plants, including marine plants, reported in the literature from 2001 to the end of 2017. During the span of the last 17 years, 175 antiplasmodial compounds were discovered from plants. These active compounds are organized in our review article according to their plant families. In addition, we also include ethnobotanical information of the antimalarial plants discussed.

Synthesis, antimalarial properties, and SAR studies of alkoxyurea-based HDAC inhibitors.

PubMed

Hansen, Finn K; Skinner-Adams, Tina S; Duffy, Sandra; Marek, Linda; Sumanadasa, Subathdrage D M; Kuna, Krystina; Held, Jana; Avery, Vicky M; Andrews, Katherine T; Kurz, Thomas

2014-03-01

Histone deacetylase (HDAC) inhibitors are an emerging class of potential antimalarial drugs. We investigated the antiplasmodial properties of 16 alkoxyurea-based HDAC inhibitors containing various cap and zinc binding groups (ZBGs). Ten compounds displayed sub-micromolar activity against the 3D7 line of Plasmodium falciparum. Structure-activity relationship studies revealed that a hydroxamic acid ZBG is crucial for antiplasmodial activity, and that the introduction of bulky alkyl substituents to cap groups increases potency against asexual blood-stage parasites. We also demonstrate that selected compounds cause hyperacetylation of P. falciparum histone H4, indicating inhibition of one or more PfHDACs. To assess the selectivity of alkoxyurea-based HDAC inhibitors for parasite over normal mammalian cells, the cytotoxicity of representative compounds was evaluated against neonatal foreskin fibroblast (NFF) cells. The most active compound, 6-((3-(4-(tert-butyl)phenyl)ureido)oxy)-N-hydroxyhexanamide (1 e, Pf3D7 IC50 : 0.16 μM) was 31-fold more toxic against the asexual blood stages than towards normal mammalian cells. Moreover, a subset of four structurally diverse HDAC inhibitors revealed moderate activity against late-stage (IV-V) gametocytes. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dibenzylideneacetone analogues as novel Plasmodium falciparum inhibitors.

PubMed

Aher, Rahul Balasaheb; Wanare, Gajanan; Kawathekar, Neha; Kumar, Ravi Ranjan; Kaushik, Naveen Kumar; Sahal, Dinkar; Chauhan, Virander Singh

2011-05-15

A series of dibenzylideneacetones (A1-A12) and some of their pyrazolines (B1-B4) were synthesized and evaluated in vitro for blood stage antiplasmodial properties in Plasmodium falciparum culture using SYBR-green-I fluorescence assay. The compound (1E, 4E)-1,5-bis(3,4-dimethoxyphenyl)penta-1,4-dien-3-one (A9) was found to be the most active with IC(50) of 1.97 μM against chloroquine-sensitive strain (3D7) and 1.69 μM against chloroquine-resistant field isolate (RKL9). The MTT based cytotoxicity assay on HeLa cell line has confirmed that A9 is selective in its action against malaria parasite (with a therapeutic index of 166). Our results revealed that these compounds exhibited promising antiplasmodial activities which can be further explored as potential leads for the development of cheaper, safe, effective and potent drugs against chloroquine-resistant malarial parasites. Copyright © 2011. Published by Elsevier Ltd.

Anti-Plasmodial Polyvalent Interactions in Artemisia annua L. Aqueous Extract – Possible Synergistic and Resistance Mechanisms

PubMed Central

Suberu, John O.; Gorka, Alexander P.; Jacobs, Lauren; Roepe, Paul D.; Sullivan, Neil

2013-01-01

Artemisia annua hot water infusion (tea) has been used in in vitro experiments against P. falciparum malaria parasites to test potency relative to equivalent pure artemisinin. High performance liquid chromatography (HPLC) and mass spectrometric analyses were employed to determine the metabolite profile of tea including the concentrations of artemisinin (47.5±0.8 mg L-1), dihydroartemisinic acid (70.0±0.3 mg L-1), arteannuin B (1.3±0.0 mg L-1), isovitexin (105.0±7.2 mg L-1) and a range of polyphenolic acids. The tea extract, purified compounds from the extract, and the combination of artemisinin with the purified compounds were tested against chloroquine sensitive and chloroquine resistant strains of P. falciparum using the DNA-intercalative SYBR Green I assay. The results of these in vitro tests and of isobologram analyses of combination effects showed mild to strong antagonistic interactions between artemisinin and the compounds (9-epi-artemisinin and artemisitene) extracted from A. annua with significant (IC50 <1 μM) anti-plasmodial activities for the combination range evaluated. Mono-caffeoylquinic acids, tri-caffeoylquinic acid, artemisinic acid and arteannuin B showed additive interaction while rosmarinic acid showed synergistic interaction with artemisinin in the chloroquine sensitive strain at a combination ratio of 1:3 (artemisinin to purified compound). In the chloroquine resistant parasite, using the same ratio, these compounds strongly antagonised artemisinin anti-plasmodial activity with the exception of arteannuin B, which was synergistic. This result would suggest a mechanism targeting parasite resistance defenses for arteannuin B’s potentiation of artemisinin. PMID:24244716

Synthesis and Antiplasmodial Evaluation of Analogues Based on the Tricyclic Core of Thiaplakortones A-D.

PubMed

Schwartz, Brett D; Coster, Mark J; Skinner-Adams, Tina S; Andrews, Katherine T; White, Jonathan M; Davis, Rohan A

2015-09-15

Six regioisomers associated with the tricyclic core of thiaplakortones A-D have been synthesized. Reaction of 1H-indole-4,7-dione and 1-tosyl-1H-indole-4,7-dione with 2-aminoethanesulfinic acid afforded a regioisomeric series, which was subsequently deprotected and oxidized to yield the tricyclic core scaffolds present in the thiaplakortones. All compounds were fully characterized using NMR and MS data. A single crystal X-ray structure was obtained on one of the N-tosyl derivatives. All compounds were screened for in vitro antiplasmodial activity against chloroquine-sensitive (3D7) and multidrug-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50 < 500 nM) but only moderate selectivity for P. falciparum versus human neonatal foreskin fibroblast cells.

Antiplasmodial activity of new 4-aminoquinoline derivatives against chloroquine resistant strain.

PubMed

Sinha, Manish; Dola, Vasanth R; Agarwal, Pooja; Srivastava, Kumkum; Haq, Wahajul; Puri, Sunil K; Katti, Seturam B

2014-07-15

Emergence and spread of multidrug resistant strains of Plasmodium falciparum has severely limited the antimalarial chemotherapeutic options. In order to overcome the obstacle, a set of new side-chain modified 4-aminoquinolines were synthesized and screened against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum. The key feature of the designed molecules is the use of methylpiperazine linked α, β(3)- and γ-amino acids to generate novel side chain modified 4-aminoquinoline analogues. Among the evaluated compounds, 20c and 30 were found more potent than CQ against K1 and displayed a four-fold and a three-fold higher activity respectively, with a good selectivity index (SI=5846 and 11,350). All synthesized compounds had resistance index between 1.06 and >14.13 as against 47.2 for chloroquine. Biophysical studies suggested that this series of compounds act on heme polymerization target. Copyright © 2014 Elsevier Ltd. All rights reserved.

Brazilian Cerrado Qualea grandiflora Mart. Leaves Exhibit Antiplasmodial and Trypanocidal Activities In vitro

PubMed Central

Cordeiro, Thuany de Moura; Borghetti, Fabian; Caldas Oliveira, Sarah C.; Bastos, Izabela Marques Dourado; de Santana, Jaime Martins; Grellier, Philippe; Charneau, Sébastien

2017-01-01

Background: The rapid spread of drug-resistant strains of protozoan parasites required the urgent need for new effective drugs. Natural products offer a variety of chemical structures, which make them a valuable source of lead compounds for the development of such new drugs. Cerrado is the second largest biome in Brazil and has the richest flora of all the world savannahs. We selected Qualea grandiflora, a plant species known for its proprieties in folk medicine and its antibacterial activity. Objective: However, its antiprotozoal activity was not yet explored. Materials and Methods: We investigated the activities of fractions from the ethyl acetate extract of Q. grandiflora leaves against human life forms of Plasmodium falciparum, Trypanosoma cruzi, and Trypanosoma brucei gambiense, and for its cytotoxicity upon the rat L6-myoblast cell line. Ten fractions were produced by ethyl acetate:hexane chromatography. Results and Conclusion: The fractions showed no cytotoxicity against L-6 cells (IC50 > 100 μg/mL) and no hemolysis propriety. Three fractions had a moderate activity against P. falciparum, anyone was active against T. cruzi but four fractions demonstrated a high activity against bloodstream forms of T. brucei gambiense (8.0< IC50 <15 μg/mL). Identification and characterization of the active compounds are currently under investigation. SUMMARY Qualea grandiflora is an endemic tree of the Brazilian Cerrado, which presents medicinal propertiesTen fractions of the ethyl acetate extract of Q. grandiflora leaves were assessed against Plasmodium falciparum, Trypanosoma Cruzi, and Trypanosoma brucei gambienseNo fraction showed relevant cytotoxicity and hemolysis activityAll the fractions presented antiplasmodial and trypanocidal activitiesThree fractions with moderate antiplasmodial activity (49< IC50 <56 μg/mL)Four fractions with high activity against bloodstream forms of T. brucei gambiense (8.0< IC50 <15 μg/mL). Abbreviations used: CQ: Chloroquine, DMSO: Dimethyl sulfoxide, HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, HMI: Modified Iscove's medium, IC50: Concentration inhibiting 50% of parasite growth, IC90: Concentration inhibiting 90% of parasite growth, MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, RPMI: Roswell Park Memorial Institute, SD: Standard deviation, SI: Ratio of cytotoxicity to biological activity − TC50/IC50, TC50: Concentration causing 50% of cell growth inhibition, TC90: Concentration causing 90% of cell growth inhibition, TLC: Thin-layer chromatography PMID:29200731

Brazilian Cerrado Qualea grandiflora Mart. Leaves Exhibit Antiplasmodial and Trypanocidal Activities In vitro.

PubMed

Cordeiro, Thuany de Moura; Borghetti, Fabian; Caldas Oliveira, Sarah C; Bastos, Izabela Marques Dourado; de Santana, Jaime Martins; Grellier, Philippe; Charneau, Sébastien

2017-01-01

The rapid spread of drug-resistant strains of protozoan parasites required the urgent need for new effective drugs. Natural products offer a variety of chemical structures, which make them a valuable source of lead compounds for the development of such new drugs. Cerrado is the second largest biome in Brazil and has the richest flora of all the world savannahs. We selected Qualea grandiflora , a plant species known for its proprieties in folk medicine and its antibacterial activity. However, its antiprotozoal activity was not yet explored. We investigated the activities of fractions from the ethyl acetate extract of Q. grandiflora leaves against human life forms of Plasmodium falciparum , Trypanosoma cruzi , and Trypanosoma brucei gambiense , and for its cytotoxicity upon the rat L6-myoblast cell line. Ten fractions were produced by ethyl acetate:hexane chromatography. The fractions showed no cytotoxicity against L-6 cells (IC 50 > 100 μg/mL) and no hemolysis propriety. Three fractions had a moderate activity against P. falciparum , anyone was active against T. cruzi but four fractions demonstrated a high activity against bloodstream forms of T. brucei gambiense (8.0< IC 50 <15 μg/mL). Identification and characterization of the active compounds are currently under investigation. Qualea grandiflora is an endemic tree of the Brazilian Cerrado, which presents medicinal propertiesTen fractions of the ethyl acetate extract of Q. grandiflora leaves were assessed against Plasmodium falciparum , Trypanosoma Cruzi , and Trypanosoma brucei gambiense No fraction showed relevant cytotoxicity and hemolysis activityAll the fractions presented antiplasmodial and trypanocidal activitiesThree fractions with moderate antiplasmodial activity (49< IC 50 <56 μg/mL)Four fractions with high activity against bloodstream forms of T. brucei gambiense (8.0< IC 50 <15 μg/mL). Abbreviations used: CQ: Chloroquine, DMSO: Dimethyl sulfoxide, HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, HMI: Modified Iscove's medium, IC 50 : Concentration inhibiting 50% of parasite growth, IC 90 : Concentration inhibiting 90% of parasite growth, MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, RPMI: Roswell Park Memorial Institute, SD: Standard deviation, SI: Ratio of cytotoxicity to biological activity - TC 50 /IC 50 , TC 50 : Concentration causing 50% of cell growth inhibition, TC 90 : Concentration causing 90% of cell growth inhibition, TLC: Thin-layer chromatography.

Antiplasmodial Drugs in the Gas Phase: A CID and DFT Study of Quinolon-4( 1H)-Imine Derivatives

NASA Astrophysics Data System (ADS)

Amorim Madeira, Paulo J.; Sitoe, Ana Raquel Fernandes; Gonçalves, Daniel; Rodrigues, Tiago; Guedes, Rita C.; Lopes, Francisca; Moreira, Rui; Bronze, M. Rosário

2014-09-01

The gas-phase behavior of 12 quinolon-4( 1H)-imine derivatives with antiplasmodial activity was investigated using electrospray ionization tandem mass spectrometry together with collision induced dissociation and density functional theory (DFT) calculations. The most probable protonation site was predicted by calculating the proton affinity (PA) values for each possible protonation site and it was found to be the imine nitrogen for all compounds under study. Fragmentation pathways of the protonated molecules were proposed and the assignment of product ion structures was performed taking into account theoretical calculations. The nature of the quinoline substituent was found to influence the gas-phase behavior of the compounds under study. The data acquired allowed to bracket the proton affinity of the quinolin-4-imine scaffold, which can be a useful starting point to choose appropriate references for determining PA values of this scaffold.

Prioritization of anti-malarial hits from nature: chemo-informatic profiling of natural products with in vitro antiplasmodial activities and currently registered anti-malarial drugs.

PubMed

Egieyeh, Samuel Ayodele; Syce, James; Malan, Sarel F; Christoffels, Alan

2016-01-29

A large number of natural products have shown in vitro antiplasmodial activities. Early identification and prioritization of these natural products with potential for novel mechanism of action, desirable pharmacokinetics and likelihood for development into drugs is advantageous. Chemo-informatic profiling of these natural products were conducted and compared to currently registered anti-malarial drugs (CRAD). Natural products with in vitro antiplasmodial activities (NAA) were compiled from various sources. These natural products were sub-divided into four groups based on inhibitory concentration (IC50). Key molecular descriptors and physicochemical properties were computed for these compounds and analysis of variance used to assess statistical significance amongst the sets of compounds. Molecular similarity analysis, estimation of drug-likeness, in silico pharmacokinetic profiling, and exploration of structure-activity landscape were also carried out on these sets of compounds. A total of 1040 natural products were selected and a total of 13 molecular descriptors were analysed. Significant differences were observed among the sub-groups of NAA and CRAD for at least 11 of the molecular descriptors, including number of hydrogen bond donors and acceptors, molecular weight, polar and hydrophobic surface areas, chiral centres, oxygen and nitrogen atoms, and shape index. The remaining molecular descriptors, including clogP, number of rotatable bonds and number of aromatic rings, did not show any significant difference when comparing the two compound sets. Molecular similarity and chemical space analysis identified natural products that were structurally diverse from CRAD. Prediction of the pharmacokinetic properties and drug-likeness of these natural products identified over 50% with desirable drug-like properties. Nearly 70% of all natural products were identified as potentially promiscuous compounds. Structure-activity landscape analysis highlighted compound pairs that form 'activity cliffs'. In all, prioritization strategies for the NAA were proposed. Chemo-informatic profiling of NAA and CRAD have produced a wealth of information that may guide decisions and facilitate anti-malarial drug development from natural products. Articulation of the information provided within an interactive data-mining environment led to a prioritized list of NAA.

Design, synthesis and antimalarial activity of novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives.

PubMed

Guillon, Jean; Cohen, Anita; Gueddouda, Nassima Meriem; Das, Rabindra Nath; Moreau, Stéphane; Ronga, Luisa; Savrimoutou, Solène; Basmaciyan, Louise; Monnier, Alix; Monget, Myriam; Rubio, Sandra; Garnerin, Timothée; Azas, Nadine; Mergny, Jean-Louis; Mullié, Catherine; Sonnet, Pascal

2017-12-01

Novel series of bis- and tris-pyrrolo[1,2-a]quinoxaline derivatives 1 were synthesized and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC 50 in the μM range. In attempting to investigate the large broad-spectrum antiprotozoal activities of these new derivatives, their properties toward Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure-activity relationships of these new synthetic compounds are discussed here. The bis-pyrrolo[1,2-a]quinoxalines 1n and 1p were identified as the most potent antimalarial candidates with selectivity index (SI) of 40.6 on W2 strain, and 39.25 on 3D7 strain, respectively. As the telomeres of the parasite could constitute an attractive target, we investigated the possibility of targeting Plasmodium telomeres by stabilizing the Plasmodium telomeric G-quadruplexes through a FRET melting assay by our new compounds.

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: towards the development of potential dual action antimalarials.

PubMed

Pérez, Bianca C; Teixeira, Cátia; Figueiras, Marta; Gut, Jiri; Rosenthal, Philip J; Gomes, José R B; Gomes, Paula

2012-08-01

A series of cinnamic acid/4-aminoquinoline conjugates conceived to link, through a proper retro-enantio dipeptide, a heterocyclic core known to prevent hemozoin formation, to a trans-cinnamic acid motif capable of inhibiting enzyme catalytic Cys residues, were synthesized as potential dual-action antimalarials. The effect of amino acid configuration and the absence of the dipeptide spacer were also assessed. The replacement of the D-amino acids by their natural L counterparts led to a decrease in both anti-plasmodial and falcipain-inhibitory activity, suggesting that the former are preferable. Molecules with such spacer were active against blood-stage Plasmodium falciparum, in vitro, and hemozoin formation, implying that the dipeptide has a key role in mediating these two activities. In turn, compounds without spacer were better falcipain-2 inhibitors, likely because these compounds are smaller and have their vinyl bonds in closer vicinity to the catalytic Cys, as suggested by molecular modeling calculations. These novel conjugates constitute promising leads for the development of new antiplasmodials targeted at blood-stage malaria parasites. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Assessment of dual life stage antiplasmodial activity of british seaweeds.

PubMed

Spavieri, Jasmine; Allmendinger, Andrea; Kaiser, Marcel; Itoe, Maurice Ayamba; Blunden, Gerald; Mota, Maria M; Tasdemir, Deniz

2013-10-22

Terrestrial plants have proven to be a prolific producer of clinically effective antimalarial drugs, but the antimalarial potential of seaweeds has been little explored. The main aim of this study was to assess the in vitro chemotherapeutical and prophylactic potential of the extracts of twenty-three seaweeds collected from the south coast of England against blood stage (BS) and liver stage (LS) Plasmodium parasites. The majority (14) of the extracts were active against BS of P. falciparum, with brown seaweeds Cystoseira tamariscifolia, C. baccata and the green seaweed Ulva lactuca being the most active (IC(50)s around 3 μg/mL). The extracts generally had high selectivity indices (>10). Eight seaweed extracts inhibited the growth of LS parasites of P. berghei without any obvious effect on the viability of the human hepatoma (Huh7) cells, and the highest potential was exerted by U. lactuca and red seaweeds Ceramium virgatum and Halopitys incurvus (IC50 values 14.9 to 28.8 μg/mL). The LS-active extracts inhibited one or more key enzymes of the malarial type-II fatty acid biosynthesis (FAS-II) pathway, a drug target specific for LS. Except for the red seaweed Halopitys incurvus, all LS-active extracts showed dual activity versus both malarial intracellular stage parasites. This is the first report of LS antiplasmodial activity and dual stage inhibitory potential of seaweeds.

Assessment of Dual Life Stage Antiplasmodial Activity of British Seaweeds

PubMed Central

Spavieri, Jasmine; Allmendinger, Andrea; Kaiser, Marcel; Itoe, Maurice Ayamba; Blunden, Gerald; Mota, Maria M.; Tasdemir, Deniz

2013-01-01

Terrestrial plants have proven to be a prolific producer of clinically effective antimalarial drugs, but the antimalarial potential of seaweeds has been little explored. The main aim of this study was to assess the in vitro chemotherapeutical and prophylactic potential of the extracts of twenty-three seaweeds collected from the south coast of England against blood stage (BS) and liver stage (LS) Plasmodium parasites. The majority (14) of the extracts were active against BS of P. falciparum, with brown seaweeds Cystoseira tamariscifolia, C. baccata and the green seaweed Ulva lactuca being the most active (IC50s around 3 μg/mL). The extracts generally had high selectivity indices (>10). Eight seaweed extracts inhibited the growth of LS parasites of P. berghei without any obvious effect on the viability of the human hepatoma (Huh7) cells, and the highest potential was exerted by U. lactuca and red seaweeds Ceramium virgatum and Halopitys incurvus (IC50 values 14.9 to 28.8 μg/mL). The LS-active extracts inhibited one or more key enzymes of the malarial type-II fatty acid biosynthesis (FAS-II) pathway, a drug target specific for LS. Except for the red seaweed Halopitys incurvus, all LS-active extracts showed dual activity versus both malarial intracellular stage parasites. This is the first report of LS antiplasmodial activity and dual stage inhibitory potential of seaweeds. PMID:24152562

In vitro anti-plasmodial activity of Dicoma anomala subsp. gerrardii (Asteraceae): identification of its main active constituent, structure-activity relationship studies and gene expression profiling.

PubMed

Becker, John V W; van der Merwe, Marina M; van Brummelen, Anna C; Pillay, Pamisha; Crampton, Bridget G; Mmutlane, Edwin M; Parkinson, Chris; van Heerden, Fanie R; Crouch, Neil R; Smith, Peter J; Mancama, Dalu T; Maharaj, Vinesh J

2011-10-11

Anti-malarial drug resistance threatens to undermine efforts to eliminate this deadly disease. The resulting omnipresent requirement for drugs with novel modes of action prompted a national consortium initiative to discover new anti-plasmodial agents from South African medicinal plants. One of the plants selected for investigation was Dicoma anomala subsp. gerrardii, based on its ethnomedicinal profile. Standard phytochemical analysis techniques, including solvent-solvent extraction, thin-layer- and column chromatography, were used to isolate the main active constituent of Dicoma anomala subsp. gerrardii. The crystallized pure compound was identified using nuclear magnetic resonance spectroscopy, mass spectrometry and X-ray crystallography. The compound was tested in vitro on Plasmodium falciparum cultures using the parasite lactate dehydrogenase (pLDH) assay and was found to have anti-malarial activity. To determine the functional groups responsible for the activity, a small collection of synthetic analogues was generated - the aim being to vary features proposed as likely to be related to the anti-malarial activity and to quantify the effect of the modifications in vitro using the pLDH assay. The effects of the pure compound on the P. falciparum transcriptome were subsequently investigated by treating ring-stage parasites (alongside untreated controls), followed by oligonucleotide microarray- and data analysis. The main active constituent was identified as dehydrobrachylaenolide, a eudesmanolide-type sesquiterpene lactone. The compound demonstrated an in vitro IC50 of 1.865 μM against a chloroquine-sensitive strain (D10) of P. falciparum. Synthetic analogues of the compound confirmed an absolute requirement that the α-methylene lactone be present in the eudesmanolide before significant anti-malarial activity was observed. This feature is absent in the artemisinins and suggests a different mode of action. Microarray data analysis identified 572 unique genes that were differentially expressed as a result of the treatment and gene ontology analysis identified various biological processes and molecular functions that were significantly affected. Comparison of the dehydrobrachylaenolide treatment transcriptional dataset with a published artesunate (also a sesquiterpene lactone) dataset revealed little overlap. These results strengthen the notion that the isolated compound and the artemisinins have differentiated modes of action. The novel mode of action of dehydrobrachylaenolide, detected during these studies, will play an ongoing role in advancing anti-plasmodial drug discovery efforts.

Investigation of the component in Artemisia annua L. leading to enhanced antiplasmodial potency of artemisinin via regulation of its metabolism.

PubMed

Cai, Tian-Yu; Zhang, Yun-Rui; Ji, Jian-Bo; Xing, Jie

2017-07-31

The chemical matrix of the herb Artemisia annua L. (A. annua), from which artemisinin (QHS) is isolated, can enhance both the bioavailability and efficacy of QHS. However, the exact mechanism of this synergism remains unknown. The biotransformation of QHS and potential "enzyme inhibitors" in plant matrix could be of great importance in understanding the improved efficacy of QHS in A. annua, which has been limited to the synergism with flavonoid components. To investigate the component in A. annua extracts (MAE) leading to enhanced antiplasmodial potency of QHS via regulation of its metabolism. The efficacy of QHS in combination with the synergistic component was also evaluated. The total MAE extract and its three MAE fractions (MAE-I eluted using 3% methanol, MAE-II eluted using 50% methanol and MAE-III eluted using 85% methanol) were obtained from dry plant materials and prepared after lyophilization. The pharmacokinetic profiles of QHS and its major phase I metabolite monohydroxylated artemisinin (QHS-M) were investigated in healthy rats after a single oral administration of QHS in each MAE extract. Major components isolated from the target MAE fraction were evaluated for their enzyme inhibition. The antimalarial activity of QHS in combination with the potential synergistic component against Plasmodium falciparum was studied in vivo (murine Plasmodium yoelii). The recrudescence and survival time of infected mice were also recorded after drug treatment. Compared to pure QHS, a 2-fold increase in QHS exposure (AUC and C max ) was found in healthy rats after a single oral dose of QHS in the total MAE extract or its fraction MAE-III. In addition, metabolic biotransformation of QHS to the metabolite QHS-M (mediated by CYP3A) was inhibited by MAE or MAE-III. Among nine major components isolated from MAE-III (five sesquiterpenenes, three flavonoids and one phenolic acid), only arteannuin B (AB) showed an inhibition of CYP3A4 (IC 50 1.2μM). The synergism between QHS and AB was supported using in vivo antiplasmodial assay and a pharmacokinetic study in mice. Unfortunately, the synergism cannot reduce the rate of recrudescence. AB was one of main contributors in A. annua leading to enhanced antiplasmodial potency of QHS via regulation of its metabolism. The final recrudescence indicated the careful use of A. annua for malaria treatment unless additional contributing components or antiplasmodial mechanism were found. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Assessment of antimalarial activity against Plasmodium falciparum and phytochemical screening of some Yemeni medicinal plants

PubMed Central

Alshawsh, Mohammed A.; Al-shamahy, Hassan A.; Alsllami, Salah F.; Lindequist, Ulrike

2009-01-01

Developing countries, where malaria is one of the most prevalent diseases, still rely on traditional medicine as a source for the treatment of this disease. In the present study, six selected plants (Acalypha fruticosa, Azadirachta indica, Cissus rotundifolia, Echium rauwalfii, Dendrosicyos socotrana and Boswellia elongata) commonly used in Yemen by traditional healers for the treatment of malaria as well as other diseases, were collected from different localities of Yemen, dried and extracted with methanol and water successfully. The antiplasmodial activity of the extracts was evaluated against fresh clinical isolates of Plasmodium falciparum. The selectivity parameters to evaluate the efficacy of these medicinal plants were measured by in vitro micro test (Mark III) according to World Health Organization (WHO) 1996 & WHO 2001 protocols of antimalarial drug tests. Among the investigated 12 extracts, three were found to have significant antiplasmodial activity with IC50 values less than 4 µg/ml, namely the water extracts of A. fruticosa, A. indica and D. socotrana. Six extracts showed moderate activity with IC50 values ranging from 10 to 30 µg/ml and three appeared to be inactive with IC50 values more than 30 µg/ml. In addition, preliminary phytochemical screening of the methanolic and aqueous extracts indicated the presence of saponins, tannins, flavonoids, terpenoids, polysaccharides and peptides. PMID:18955251

Evaluation of the antiplasmodial and cytotoxicity potentials of husk fiber extracts from Cocos nucifera, a medicinal plant used in Nigeria to treat human malaria.

PubMed

Adebayo, J O; Santana, A E G; Krettli, A U

2012-03-01

Nigeria is an African country where transmission of malaria occurs all year round and where most inhabitants use plants as remedies against parasitic diseases, including malaria. Some of such medicinal plants have their antimalarial efficacies already demonstrated experimentally, active compounds isolated and the mechanism of drug action suggested. Decoction of Cocos nucifera husk is used in the middle belt region of Nigeria as an antimalarial remedy. In our current studies, we tested extracts from husks of four varieties of C. nucifera, all collected in Brazil, where the plant fruit is popularly named 'coco'. The husks of coco mestiço, amarelo, anão and gigante collected in the Northeast of Brazil were used to prepare extracts at the Chemistry Department, Federal University of Alagoas (UFAL), which were then tested for their antiplasmodial activities, cytotoxicities and hemolytic activities in vitro. Only the hexane extract of coco mestiço was active against the blood forms of Plasmodium falciparum human malaria parasite maintained in continuous culture. Most extracts presented selectivity indices of <10, while hexane extract of coco mestiço had a selectivity index of 35, meaning that the extract is not toxic. The isolation of the active compounds from coco mestiço husks has not yet been done.

The use of microfluorometric method for activity-guided isolation of antiplasmodial compound from plant extracts.

PubMed

Shuaibu, M N; Wuyep, P A; Yanagi, T; Hirayama, K; Tanaka, T; Kouno, I

2008-05-01

In vitro antiplasmodial activity of methanolic extracts of 16 medicinal plants was evaluated by fluorometric assay using PicoGreen. The IC50s, as determined by parasite DNA concentration, ranged from <11 to >200 and <13 to >200 microg/ml for Plasmodium falciparum 3D7 and K1, respectively; and the most active extracts were those from Anogeissus leiocarpus and Terminalia avicennoides (<11-> or =14 microg/ml). Aqueous, butanolic, ethyl acetate, and methanolic fractions of these two extracts revealed butanolic fraction to have a relatively better activity (IC50, 10-12 microg/ml). Activity-guided chromatographic separation of the butanolic fraction on Sephadex LH-20 followed by nuclear magnetic resonance and correlation high-performance liquid chromatography revealed the presence of known hydrolysable tannins and some related compounds-castalagin, ellagic acid, flavogallonic acid, punicalagin, terchebulin, and two other fractions. The IC50s of all these compounds ranged between 8-21 microg/ml (8-40 microM) against both the strains. Toxicity assay with mouse fibroblasts showed all the extracts and isolated compounds to have IC50 > or = 1500 microg/ml, except for Momordica balsamina with <1500 microg/l. All the extracts and isolated compounds did not affect the integrity of human erythrocyte membrane at the observed IC50s. However, adverse effects manifest in a concentration-dependent fashion (from IC50 > or = 500 microg/ml).

Chemical composition and anticancer, antiinflammatory, antioxidant and antimalarial activities of leaves essential oil of Cedrelopsis grevei.

PubMed

Afoulous, Samia; Ferhout, Hicham; Raoelison, Emmanuel Guy; Valentin, Alexis; Moukarzel, Béatrice; Couderc, François; Bouajila, Jalloul

2013-06-01

The essential oil from Cedrelopsis grevei leaves, an aromatic and medicinal plant from Madagascar, is widely used in folk medicine. Essential oil was characterized by GC-MS and quantified by GC-FID. Sixty-four components were identified. The major constituents were: (E)-β-farnesene (27.61%), δ-cadinene (14.48%), α-copaene (7.65%) and β-elemene (6.96%). The essential oil contained a complex mixture consisting mainly sesquiterpene hydrocarbons (83.42%) and generally sesquiterpenes (98.91%). The essential oil was tested cytotoxic (on human breast cancer cells MCF-7), antimalarial (Plasmodium falciparum), antiinflammatory and antioxidant (ABTS and DPPH assays) activities. C. grevei essential oil was active against MCF-7 cell lines (IC50=21.5 mg/L), against P. falciparum, (IC50=17.5mg/L) and antiinflammatory (IC50=21.33 mg/L). The essential oil exhibited poor antioxidant activity against DPPH (IC50>1000 mg/L) and ABTS (IC50=110 mg/L) assays. A bibliographical review was carried out of all essential oils identified and tested with respect to antiplasmodial, anticancer and antiinflammatory activities. The aim was to establish correlations between the identified compounds and their biological activities (antiplasmodial, anticancer and antiinflammatory). According to the obtained correlations, 1,4-cadinadiene (R(2)=0.61) presented a higher relationship with antimalarial activity. However, only (Z)-β-farnesene (R(2)=0.73) showed a significant correlation for anticancer activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Plants as antimalarial agents in Sub-Saharan Africa.

PubMed

Chinsembu, Kazhila C

2015-12-01

Although the burden of malaria is decreasing, parasite resistance to current antimalarial drugs and resistance to insecticides by vector mosquitoes threaten the prospects of malaria elimination in endemic areas. Corollary, there is a scientific departure to discover new antimalarial agents from nature. Because the two antimalarial drugs quinine and artemisinin were discovered through improved understanding of the indigenous knowledge of plants, bioprospecting Sub-Saharan Africa's enormous plant biodiversity may be a source of new and better drugs to treat malaria. This review analyses the medicinal plants used to manage malaria in Sub-Saharan Africa. Chemical compounds with antiplasmodial activity are described. In the Sub-Saharan African countries cited in this review, hundreds of plants are used as antimalarial remedies. While the number of plant species is not exhaustive, plants used in more than one country probably indicate better antimalarial efficacy and safety. The antiplasmodial data suggest an opportunity for inventing new antimalarial drugs from Sub-Saharan-African flora. Copyright © 2015 Elsevier B.V. All rights reserved.

Quantification of the antiplasmodial alkaloid carpaine in papaya (Carica papaya) leaves.

PubMed

Julianti, Tasqiah; Oufir, Mouhssin; Hamburger, Matthias

2014-08-01

Daily consumption of papaya (Carica papaya) leaves as greens and an herbal infusion is common in some parts of Indonesia as a means for preventing malaria. Antiplasmodial activity of the leaf extracts and of the main alkaloid carpaine were recently confirmed. A quantitative assay for determination of carpaine in papaya leaves was developed and validated. The assay involved pressurized liquid extraction and quantification with the aid of ultrahigh-performance liquid chromatography-tandem mass spectroscopy. Extraction conditions were optimized with respect to solvent, temperature, and number of extraction cycles. The ultrahigh-performance liquid chromatography-tandem mass spectroscopy assay was validated over a range of 20-5000 ng/mL (R(2) of 0.9908). A total of 29 papaya leaf samples were analyzed, and carpaine concentration in dry leaves was found to range from 0.02 to 0.31%. No obvious dependence on geographic origin and leaf maturity was observed. Georg Thieme Verlag KG Stuttgart · New York.

Antimicrobial peptides: a new class of antimalarial drugs?

PubMed Central

Vale, Nuno; Aguiar, Luísa; Gomes, Paula

2014-01-01

A range of antimicrobial peptides (AMP) exhibit activity on malaria parasites, Plasmodium spp., in their blood or mosquito stages, or both. These peptides include a diverse array of both natural and synthetic molecules varying greatly in size, charge, hydrophobicity, and secondary structure features. Along with an overview of relevant literature reports regarding AMP that display antiplasmodial activity, this review makes a few considerations about those molecules as a potential new class of antimalarial drugs. PMID:25566072

Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains.

PubMed

Tasso, Bruno; Novelli, Federica; Tonelli, Michele; Barteselli, Anna; Basilico, Nicoletta; Parapini, Silvia; Taramelli, Donatella; Sparatore, Anna; Sparatore, Fabio

2015-09-01

Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria-related deaths, has developed resistance against this drug. Twenty-seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro-2H-quinolizine and 1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one, were synthesized and tested for activity against D-10 (CQ-susceptible) and W-2 (CQ-resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub-micromolar IC50 values. Eleven compounds were found to be 2.7- to 13.4-fold more potent than CQ against the W-2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC-1 and HepG2) along with easier synthetic accessibility. Replacement of the 4-NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Benzoxazine derivatives of phytophenols show anti-plasmodial activity via sodium homeostasis disruption.

PubMed

Sharma, Vijeta; Amarnath, Nagarjuna; Shukla, Swapnil; Ayana, R; Kumar, Naveen; Yadav, Nisha; Kannan, Deepika; Sehrawat, Seema; Pati, Soumya; Lochab, Bimlesh; Singh, Shailja

2018-05-15

Development of new class of anti-malarial drugs is an essential requirement for the elimination of malaria. Bioactive components present in medicinal plants and their chemically modified derivatives could be a way forward towards the discovery of effective anti-malarial drugs. Herein, we describe a new class of compounds, 1,3-benzoxazine derivatives of pharmacologically active phytophenols eugenol (compound 3) and isoeugenol (compound 4) synthesised on the principles of green chemistry, as anti-malarials. Compound 4, showed highest anti-malarial activity with no cytotoxicity towards mammalian cells. Compound 4 induced alterations in the intracellular Na + levels and mitochondrial depolarisation in intraerythrocytic Plasmodium falciparum leading to cell death. Knowing P-type cation ATPase PfATP4 is a regulator for sodium homeostasis, binding of compound 3, compound 4 and eugenol to PfATP4 was analysed by molecular docking studies. Compounds showed binding to the catalytic pocket of PfATP4, however compound 4 showed stronger binding due to the presence of propylene functionality, which corroborates its higher anti-malarial activity. Furthermore, anti-malarial half maximal effective concentration of compound 4 was reduced to 490 nM from 17.54 µM with nanomaterial graphene oxide. Altogether, this study presents anti-plasmodial potential of benzoxazine derivatives of phytophenols and establishes disruption of parasite sodium homeostasis as their mechanism of action. Copyright © 2018 Elsevier Ltd. All rights reserved.

In vitro antiplasmodial, antileishmanial and antitrypanosomal activities of selected medicinal plants used in the traditional Arabian Peninsular region

PubMed Central

2012-01-01

Background Worldwide particularly in developing countries, a large proportion of the population is at risk for tropical parasitic diseases. Several medicinal plants are still used traditionally against protozoal infections in Yemen and Saudi Arabia. Thus the present study investigated the in vitro antiprotozoal activity of twenty-five plants collected from the Arabian Peninsula. Methods Plant materials were extracted with methanol and screened in vitro against erythrocytic schizonts of Plasmodium falciparum, intracellular amastigotes of Leishmania infantum and Trypanosoma cruzi and free trypomastigotes of T. brucei. Cytotoxic activity was determined against MRC-5 cells to assess selectivity. The criterion for activity was an IC50 < 10 μg/ml (<5 μg/ml for T. brucei) and selectivity index of >4. Results Antiplasmodial activity was found in the extracts of Chrozophora oblongifolia, Ficus ingens, Lavandula dentata and Plectranthus barbatus. Amastigotes of T. cruzi were affected by Grewia erythraea, L. dentata, Tagetes minuta and Vernonia leopoldii. Activity against T. brucei was obtained in G. erythraea, L. dentata, P. barbatus and T. minuta. No relevant activity was found against L. infantum. High levels of cytotoxicity (MRC-5 IC50 < 10 μg/ml) and hence non-specific activities were noted in Cupressus sempervirens, Kanahia laniflora and Kniphofia sumarae. Conclusion The results endorse that medicinal plants can be promising sources of natural products with antiprotozoal activity potential. The results support to some extent the traditional uses of some plants for the treatment of parasitic protozoal diseases. PMID:22520595

Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones

PubMed Central

Sarkar, Souvik; Siddiqui, Asim A.; Saha, Shubhra J.; De, Rudranil; Mazumder, Somnath; Banerjee, Chinmoy; Iqbal, Mohd S.; Nag, Shiladitya; Adhikari, Susanta

2016-01-01

We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite in vitro, as well as in vivo in a murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (KD [equilibrium dissociation constant] = 1.17 ± 0.8 μM), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structure-activity relationship studies indicated that a nitrogen- and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [3H]hypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity in vitro against a chloroquine/pyrimethamine-resistant strain of Plasmodium falciparum (K1). We also evaluated in vivo antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of Plasmodium yoelii was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During in vitro and in vivo toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria. PMID:27139466

Antiplasmodial, cytotoxic activities and characterization of a new naturally occurring quinone methide pentacyclic triterpenoid derivative isolated from Salacia leptoclada Tul. (Celastraceae) originated from Madagascar

PubMed Central

Ruphin, Fatiany Pierre; Baholy, Robijaona; Emmanue, Andrianarivo; Amelie, Raharisololalao; Martin, Marie-Therese; Koto-te-Nyiwa, Ngbolua

2013-01-01

Objective To validate scientifically the traditional use of Salacia leptoclada Tul. (Celastraceae) (S. leptoclada) and to isolate and elucidate the structure of the biologically active compound. Methods Bioassay-guided fractionation of the acetonic extract of the stem barks of S. leptoclada was carried out by a combination of chromatography technique and biological experiments in viro using Plasmodium falciparum and P388 leukemia cell lines as models. The structure of the biologically active pure compound was elucidated by 1D and 2D NMR spectroscopy and mass spectrometry. Results Biological screening of S. leptoclada extracts resulted in the isolation of a pentacyclic triterpenic quinone methide. The pure compound exhibited both in vitro a cytotoxic effect on murine P388 leukemia cells with IC50 value of (0.041±0.020) µg/mL and an antiplasmodial activity against the chloroquine-resistant strain FC29 of Plasmodium falciparum with an IC50 value of (0.052±0.030) µg/mL. Despite this interesting anti-malarial property of the lead compound, the therapeutic index was weak (0.788). In the best of our knowledge, the quinone methide pentacyclic triterpenoid derivative compound is reported for the first time in S. leptoclada. Conclusions The results suggest that furthers studies involving antineoplastic activity is needed for the development of this lead compound as anticancer drug. PMID:24075342

Antiplasmodial, cytotoxic activities and characterization of a new naturally occurring quinone methide pentacyclic triterpenoid derivative isolated from Salacia leptoclada Tul. (Celastraceae) originated from Madagascar.

PubMed

Ruphin, Fatiany Pierre; Baholy, Robijaona; Emmanue, Andrianarivo; Amelie, Raharisololalao; Martin, Marie-Therese; Koto-te-Nyiwa, Ngbolua

2013-10-01

To validate scientifically the traditional use of Salacia leptoclada Tul. (Celastraceae) (S. leptoclada) and to isolate and elucidate the structure of the biologically active compound. Bioassay-guided fractionation of the acetonic extract of the stem barks of S. leptoclada was carried out by a combination of chromatography technique and biological experiments in viro using Plasmodium falciparum and P388 leukemia cell lines as models. The structure of the biologically active pure compound was elucidated by 1D and 2D NMR spectroscopy and mass spectrometry. Biological screening of S. leptoclada extracts resulted in the isolation of a pentacyclic triterpenic quinone methide. The pure compound exhibited both in vitro a cytotoxic effect on murine P388 leukemia cells with IC50 value of (0.041±0.020) μg/mL and an antiplasmodial activity against the chloroquine-resistant strain FC29 of Plasmodium falciparum with an IC50 value of (0.052±0.030) μg/mL. Despite this interesting anti-malarial property of the lead compound, the therapeutic index was weak (0.788). In the best of our knowledge, the quinone methide pentacyclic triterpenoid derivative compound is reported for the first time in S. leptoclada. The results suggest that furthers studies involving antineoplastic activity is needed for the development of this lead compound as anticancer drug. Copyright © 2013 Asian Pacific Tropical Biomedical Magazine. Published by Elsevier B.V. All rights reserved.

Pentamethylcyclopentadienyl-rhodium and iridium complexes containing (N^N and N^O) bound chloroquine analogue ligands: synthesis, characterization and antimalarial properties.

PubMed

Ekengard, Erik; Kumar, Kamlesh; Fogeron, Thibault; de Kock, Carmen; Smith, Peter J; Haukka, Matti; Monari, Magda; Nordlander, Ebbe

2016-03-07

The synthesis and characterization of twenty new pentamethylcyclopentadienyl-rhodium and iridium complexes containing N^N and N^O-chelating chloroquine analogue ligands are described. The in vitro antimalarial activity of the new ligands as well as the complexes was evaluated against the chloroquine sensitive (CQS) NF54 and the chloroquine resistant (CQR) Dd2 strains of Plasmodium falciparum. The antimalarial activity was found to be good to moderate; although all complexes are less active than artesunate, some of the ligands and complexes showed better activity than chloroquine (CQ). In particular, rhodium complexes were found to be considerably more active than iridium complexes against the CQS NF54 strain. Salicylaldimine Schiff base ligands having electron-withdrawing groups (F, Cl, Br, I and NO2) in para position of the salicyl moiety and their rhodium complexes showed good antiplasmodial activity against both the CQS-NF54 and the CQR-Dd2 strains. The crystal structures of (η(5)-pentamethylcyclopentadienyl){N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)} chlororhodium(III) chloride and (η(5)-pentamethylcyclopentadienyl){(4-chloro-2-(((2-((7-chloroquinolin-4-yl)amino)ethyl)imino)methyl)phenolate)}chlororhodium(III) chloride are reported. The crystallization of the amino-pyridyl complex (η(5)-pentamethylcyclopentadienyl){(N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)}chloroiridium(III) chloride in acetone resulted in the formation of the imino-pyridyl derivative (η(5)-pentamethylcyclopentadienyl){(N1-(7-chloroquinolin-4-yl)-N2-(pyridin-2-ylmethylene)ethane-1,2-diamine)}chloroiridium(III) chloride, the crystal structure of which is also reported.

Antiplasmodial activity of tick defensins in a mouse model of malaria.

PubMed

Couto, Joana; Tonk, Miray; Ferrolho, Joana; Antunes, Sandra; Vilcinskas, Andreas; de la Fuente, José; Domingos, Ana; Cabezas-Cruz, Alejandro

2018-05-01

Malaria is a mosquito-borne disease affecting millions of people mainly in Sub-Saharan Africa, Asia and some South American countries. Drug resistance to first-line antimalarial drugs (e.g. chloroquine, sulfadoxine-pyrimethamine and artemisinin) is a major constrain in malaria control. Antimicrobial peptides (AMPs) have shown promising results in controlling Plasmodium spp. parasitemia in in vitro and in vivo models of infection. Defensins are AMPs that act primarily by disrupting the integrity of cell membranes of invasive microbes. We previously showed that defensins from the tick Ixodes ricinus inhibited significantly the growth of P. falciparum in vitro, a property that was conserved during evolution. Here, we tested the activity of three I. ricinus defensins against P. chabaudi in mice. A single dose of defensin (120 μl of 1 mg/ml solution) was administered intravenously to P. chabaudi-infected mice, and the parasitemia was followed for 24 h post-treatment. Defensin treatment inhibited significantly the replication (measured as increases in parasitemia) of P. chabaudi after 1 h and 12 h of treatment. Furthermore, defensin injection was not associated with toxicity. These results agreed with the previous report of antiplasmodial activity of tick defensins against P. falciparum in vitro and justify further studies for the use of tick defensins to control malaria. Copyright © 2018 Elsevier GmbH. All rights reserved.

Erythrocyte membrane modifying agents and the inhibition of Plasmodium falciparum growth: structure-activity relationships for betulinic acid analogues.

PubMed

Ziegler, Hanne L; Franzyk, Henrik; Sairafianpour, Majid; Tabatabai, Mehrnoush; Tehrani, Mahboubeh D; Bagherzadeh, Karim; Hägerstrand, Henry; Staerk, Dan; Jaroszewski, Jerzy W

2004-01-02

The natural triterpene betulinic acid and its analogues (betulinic aldehyde, lupeol, betulin, methyl betulinate and betulinic acid amide) caused concentration-dependent alterations of erythrocyte membrane shape towards stomatocytes or echinocytes according to their hydrogen bonding properties. Thus, the analogues with a functional group having a capacity of donating a hydrogen bond (COOH, CH(2)OH, CONH(2)) caused formation of echinocytes, whereas those lacking this ability (CH(3), CHO, COOCH(3)) induced formation of stomatocytes. Both kinds of erythrocyte alterations were prohibitive with respect to Plasmodium falciparum invasion and growth; all compounds were inhibitory with IC(50) values in the range 7-28 microM, and the growth inhibition correlated well with the extent of membrane curvature changes assessed by transmission electron microscopy. Erythrocytes pre-loaded with betulinic acid or its analogues and extensively washed in order to remove excess of the chemicals could not serve as hosts for P. falciparum parasites. Betulinic acid and congeners can be responsible for in vitro antiplasmodial activity of plant extracts, as shown for Zataria multiflora Boiss. (Labiatae) and Zizyphus vulgaris Lam. (Rhamnaceae). The activity is evidently due to the incorporation of the compounds into the lipid bilayer of erythrocytes, and may be caused by modifications of cholesterol-rich membrane rafts, recently shown to play an important role in parasite vacuolization. The established link between erythrocyte membrane modifications and antiplasmodial activity may provide a novel target for potential antimalarial drugs.

Conformational flexibility determines selectivity and antibacterial, antiplasmodial, and anticancer potency of cationic α-helical peptides.

PubMed

Vermeer, Louic S; Lan, Yun; Abbate, Vincenzo; Ruh, Emrah; Bui, Tam T; Wilkinson, Louise J; Kanno, Tokuwa; Jumagulova, Elmira; Kozlowska, Justyna; Patel, Jayneil; McIntyre, Caitlin A; Yam, W C; Siu, Gilman; Atkinson, R Andrew; Lam, Jenny K W; Bansal, Sukhvinder S; Drake, Alex F; Mitchell, Graham H; Mason, A James

2012-10-05

We used a combination of fluorescence, circular dichroism (CD), and NMR spectroscopies in conjunction with size exclusion chromatography to help rationalize the relative antibacterial, antiplasmodial, and cytotoxic activities of a series of proline-free and proline-containing model antimicrobial peptides (AMPs) in terms of their structural properties. When compared with proline-free analogs, proline-containing peptides had greater activity against Gram-negative bacteria, two mammalian cancer cell lines, and intraerythrocytic Plasmodium falciparum, which they were capable of killing without causing hemolysis. In contrast, incorporation of proline did not have a consistent effect on peptide activity against Mycobacterium tuberculosis. In membrane-mimicking environments, structures with high α-helix content were adopted by both proline-free and proline-containing peptides. In solution, AMPs generally adopted disordered structures unless their sequences comprised more hydrophobic amino acids or until coordinating phosphate ions were added. Proline-containing peptides resisted ordering induced by either method. The roles of the angle subtended by positively charged amino acids and the positioning of the proline residues were also investigated. Careful positioning of proline residues in AMP sequences is required to enable the peptide to resist ordering and maintain optimal antibacterial activity, whereas varying the angle subtended by positively charged amino acids can attenuate hemolytic potential albeit with a modest reduction in potency. Maintaining conformational flexibility improves AMP potency and selectivity toward bacterial, plasmodial, and cancerous cells while enabling the targeting of intracellular pathogens.

Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones.

PubMed

Sarkar, Souvik; Siddiqui, Asim A; Saha, Shubhra J; De, Rudranil; Mazumder, Somnath; Banerjee, Chinmoy; Iqbal, Mohd S; Nag, Shiladitya; Adhikari, Susanta; Bandyopadhyay, Uday

2016-07-01

We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite in vitro, as well as in vivo in a murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (KD [equilibrium dissociation constant] = 1.17 ± 0.8 μM), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structure-activity relationship studies indicated that a nitrogen- and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [(3)H]hypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity in vitro against a chloroquine/pyrimethamine-resistant strain of Plasmodium falciparum (K1). We also evaluated in vivo antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of Plasmodium yoelii was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During in vitro and in vivo toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

In vitro antimalarial activity of medicinal plant extracts against Plasmodium falciparum.

PubMed

Bagavan, Asokan; Rahuman, Abdul Abdul; Kaushik, Naveen Kumar; Sahal, Dinkar

2011-01-01

Malaria is a major global public health problem, and the alarming spread of drug resistance and limited number of effective drugs now available underline how important it is to discover new antimalarial compounds. In the present study, ten plants were extracted with ethyl acetate and methanol and tested for their antimalarial activity against chloroquine (CQ)-sensitive (3D7) and CQ-resistant (Dd2 and INDO) strains of Plasmodium falciparum in culture using the fluorescence-based SYBR Green assay. Plant extracts showed moderate to good antiparasitic effects. Promising antiplasmodial activity was found in the extracts from two plants, Phyllanthus emblica leaf 50% inhibitory concentration (IC₅₀) 3D7: 7.25 μg/mL (ethyl acetate extract), 3.125 μg/mL (methanol extract), and Syzygium aromaticum flower bud, IC₅₀ 3D7:13 μg/mL, (ethyl acetate extract) and 6.25 μg/mL (methanol extract). Moderate activity (30-75 μg/mL) was found in the ethyl acetate and methanol extracts of Abrus precatorius (seed) and Gloriosa superba (leaf); leaf ethyl acetate extracts of Annona squamosa and flower of Musa paradisiaca. The above mentioned plant extracts were also found to be active against CQ-resistant strains (Dd2 and INDO). Cytotoxicity study with P. emblica leaf and S. aromaticum flower bud, extracts showed good therapeutic indices. These results demonstrate that leaf ethyl acetate and methanol extracts of P. emblica and flower bud extract of S. aromaticum may serve as antimalarial agents even in their crude form. The isolation of compounds from P. emblica and S. aromaticum seems to be of special interest for further antimalarial studies.

Antimalarial efficacy of Albizia lebbeck (Leguminosae) against Plasmodium falciparum in vitro & P. berghei in vivo.

PubMed

Kalia, Shagun; Walter, Neha Sylvia; Bagai, Upma

2015-12-01

Albizia lebbeck Benth. (Leguminosae) has long been used in Indian traditional medicine. The current study was designed to test antimalarial activity of ethanolic bark extract of A. lebbeck (EBEAL). EBEAL was prepared by soxhlet extraction and subjected to phytochemical analysis. The extract was evaluated for its in vitro antimalarial activity against Plasmodium falciparum chloroquine (CQ) sensitive (MRC2) and CQ resistant (RKL9) strains. Cytotoxicity (CC 50 ) of extract against HeLa cells was evaluated. Median lethal dose (LD 50 ) was determined to assess safety of EBEAL in BALB/c mice. Schizonticidal (100-1000 mg/kg) and preventive (100-750 mg/kg) activities of EBEAL were evaluated against P. berghei. Curative activity (100-750 mg/kg) of extract was also evaluated. Phytochemical screening revealed presence of alkaloids, flavonoids, phenols, saponins, terpenes and phytosterols. The extract exhibited IC 50 of 8.2 µg/ml (MRC2) and 5.1 µg/ml (RKL9). CC 50 of extract on HeLa cell line was calculated to be >1000 µg/ml. EBEAL showed selectivity indices (SI) of >121.9 and >196.07 against MRC2 and RKL9 strains of P. falciparum, respectively. LD 50 of EBEAL was observed to be >5 g/kg. Dose-dependent chemosuppression was observed with significant ( p<0.001) schizonticidal activity at 1000 mg/kg with ED 50 >100 mg/kg. Significant (P<0.001) curative and repository activities were exhibited by 750 mg/kg concentration of extract on D7. The present investigation reports antiplasmodial efficacy of EBEAL in vitro against P. falciparum as evident by high SI values. ED 50 of <100 mg/kg against P. berghei categorizes EBEAL as active antimalarial. Further studies need to be done to exploit its antiplasmodial activity further.

Antimalarial activity of sesquiterpene lactones from Vernonia cinerea.

PubMed

Chea, Aun; Hout, Sotheara; Long, Christophe; Marcourt, Laurence; Faure, Robert; Azas, Nadine; Elias, Riad

2006-10-01

Two new sesquiterpene lactones, vernolides C and D as well as six known ones were isolated from the dichloromethane fraction of an aqueous extract from Vernonia cinerea. Their structures were elucidated by spectroscopic methods. Among the known sesquiterpene lactones, three of them were described in this plant for the first time. In vitro antiplasmodial evaluation showed that the three major compounds 1, 7 and 8 were active against chloroquine resistant Plasmodium falciparum strain (W2) with IC(50) 3.9, 3.7 and 3.5 microM, respectively.

Antiplasmodial activity and cytotoxicity of ethanol extract of Zea mays root

PubMed Central

Okokon, Jude Efiom; Antia, Bassey Sunday; Azare, Bala Adamu; Okokon, Patience Jude

2017-01-01

Objective: Zea mays root decoction that has been traditionally used for the treatment of malaria by various tribes in Nigeria, was evaluated for antimalarial potential against malaria parasites using in vivo and in vitro models. Materials and Methods: The root extract of Zea mays was investigated for antimalarial activity against Plasmodium berghei in mice using rodent malaria models; suppressive, prophylactic and curative tests and in vitro antiplasmodial activity against chloroquine-sensitive (Pf 3D7) and resistant (Pf INDO) strains of Plasmodium falciparum using SYBR green assay method. Median lethal dose and cytotoxic activity against HeLa and HEKS cells were assessed and phytochemical screening was also carried out using standard procedures. Results: The LD50 value of root extract was found to be 474.34 mg/kg. The crude extract (45-135 mg/kg, p.o) showed significant (p<0.05-0.001) antimalarial activity against P. berghei infection in suppressive, prophylactic and curative tests with a prolonged survival time. The crude extract also showed moderate activity against both chloroquine-sensitive (Pf 3D7) and resistant (Pf INDO) strains of P. falciparum with an IC50 value of 71.62±3.38 μg/ml (for Pf 3D7) and 63.76±4.12 μg/ml (for Pf INDO). The crude extract was not cytotoxic to the two cell lines tested with TC50 of >100 μg/ml against both HeLa and HEKS cell lines. Conclusion: These results suggest that the root extract of Zea mays possesses antimalarial activity against both chloroquine-sensitive and resistant malaria and these data justify its use in ethnomedicine to treat malaria infections. PMID:28748174

Antiplasmodial activity and cytotoxicity of ethanol extract of Zea mays root.

PubMed

Okokon, Jude Efiom; Antia, Bassey Sunday; Azare, Bala Adamu; Okokon, Patience Jude

2017-01-01

Zea mays root decoction that has been traditionally used for the treatment of malaria by various tribes in Nigeria, was evaluated for antimalarial potential against malaria parasites using in vivo and in vitro models. The root extract of Zea mays was investigated for antimalarial activity against Plasmodium berghei in mice using rodent malaria models; suppressive, prophylactic and curative tests and in vitro antiplasmodial activity against chloroquine-sensitive (Pf 3D7) and resistant (Pf INDO) strains of Plasmodium falciparum using SYBR green assay method. Median lethal dose and cytotoxic activity against HeLa and HEKS cells were assessed and phytochemical screening was also carried out using standard procedures. The LD 50 value of root extract was found to be 474.34 mg/kg. The crude extract (45-135 mg/kg, p.o) showed significant (p<0.05-0.001) antimalarial activity against P. berghei infection in suppressive, prophylactic and curative tests with a prolonged survival time. The crude extract also showed moderate activity against both chloroquine-sensitive (Pf 3D7) and resistant (Pf INDO) strains of P. falciparum with an IC 50 value of 71.62±3.38 μg/ml (for Pf 3D7) and 63.76±4.12 μg/ml (for Pf INDO). The crude extract was not cytotoxic to the two cell lines tested with TC 50 of >100 μg/ml against both HeLa and HEKS cell lines. These results suggest that the root extract of Zea mays possesses antimalarial activity against both chloroquine-sensitive and resistant malaria and these data justify its use in ethnomedicine to treat malaria infections.

QSAR-Driven Design and Discovery of Novel Compounds With Antiplasmodial and Transmission Blocking Activities.

PubMed

Lima, Marilia N N; Melo-Filho, Cleber C; Cassiano, Gustavo C; Neves, Bruno J; Alves, Vinicius M; Braga, Rodolpho C; Cravo, Pedro V L; Muratov, Eugene N; Calit, Juliana; Bargieri, Daniel Y; Costa, Fabio T M; Andrade, Carolina H

2018-01-01

Malaria is a life-threatening infectious disease caused by parasites of the genus Plasmodium , affecting more than 200 million people worldwide every year and leading to about a half million deaths. Malaria parasites of humans have evolved resistance to all current antimalarial drugs, urging for the discovery of new effective compounds. Given that the inhibition of deoxyuridine triphosphatase of Plasmodium falciparum ( Pf dUTPase) induces wrong insertions in plasmodial DNA and consequently leading the parasite to death, this enzyme is considered an attractive antimalarial drug target. Using a combi-QSAR (quantitative structure-activity relationship) approach followed by virtual screening and in vitro experimental evaluation, we report herein the discovery of novel chemical scaffolds with in vitro potency against asexual blood stages of both P. falciparum multidrug-resistant and sensitive strains and against sporogonic development of P. berghei . We developed 2D- and 3D-QSAR models using a series of nucleosides reported in the literature as Pf dUTPase inhibitors. The best models were combined in a consensus approach and used for virtual screening of the ChemBridge database, leading to the identification of five new virtual Pf dUTPase inhibitors. Further in vitro testing on P. falciparum multidrug-resistant (W2) and sensitive (3D7) parasites showed that compounds LabMol-144 and LabMol-146 demonstrated fair activity against both strains and presented good selectivity versus mammalian cells. In addition, LabMol-144 showed good in vitro inhibition of P. berghei ookinete formation, demonstrating that hit-to-lead optimization based on this compound may also lead to new antimalarials with transmission blocking activity.

UCT943, a next generation Plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria.

PubMed

Brunschwig, Christel; Lawrence, Nina; Taylor, Dale; Abay, Efrem; Njoroge, Mathew; Basarab, Gregory S; Le Manach, Claire; Paquet, Tanya; Gonzàlez Cabrera, Diego; Nchinda, Aloysius T; de Kock, Carmen; Wiesner, Lubbe; Denti, Paolo; Waterson, David; Blasco, Benjamin; Leroy, Didier; Witty, Michael J; Donini, Cristina; Duffy, James; Wittlin, Sergio; White, Karen L; Charman, Susan A; Jiménez-Díaz, Maria Belén; Angulo-Barturen, Iñigo; Herreros, Esperanza; Gamo, Francisco Javier; Rochford, Rosemary; Mancama, Dalu; Coetzer, Theresa L; van der Watt, Mariëtte E; Reader, Janette; Birkholtz, Lyn-Marie; Marsh, Kennan C; Solapure, Suresh M; Vanaerschot, Manu; Fidock, David A; Fish, Paul V; Siegl, Peter; Smith, Dennis A; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N; Marfurt, Jutta; Silue, Kigbafori D; Street, Leslie J; Chibale, Kelly

2018-06-25

The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite lifecycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activity than MMV048 and was more potent against resistant P. falciparum and P. vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in P. berghei and humanized P. falciparum NOD- scid IL-2Rγ null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vitro intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next generation Plasmodium PI4K inhibitor, the combined preclinical data suggest that UCT943 has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent and block the transmission of malaria. Copyright © 2018 American Society for Microbiology.

Antimalarial activity of Syzygium guineense during early and established Plasmodium infection in rodent models.

PubMed

Tadesse, Solomon Asmamaw; Wubneh, Zewdu Birhanu

2017-01-05

In Ethiopia, the leaves of Syzygium guineense have been found useful for the prevention and cure of malaria, and demonstrated antiplasmodial activity in vitro. Nevertheless, no scientific study has been conducted to confirm its antimalarial activity in vivo. Therefore, the objective of the study was to evaluate the antimalarial effect of Syzygium guineense leaf extract in mice. Inoculation of the study mice was carried out by using the malaria parasite, Plasmodium berghei. The plant extract was prepared at 200, 400 and 600 mg/kg. Chloroquine and distilled water was administered to the positive and negative control groups respectively. Parameters like parasitaemia, survival time and body weight were determined following standard tests (4-day suppressive, Rane's and repository tests). Syzygium guineense crude leaf extract displayed considerable (p < 0.05) parasite suppression at doses of 600 and 400 mg/kg in a 4-day suppressive test with chemosuppressive value of 59.39 and 49.09% respectively. S. guineense crude leaf extract also showed dose-dependent schizontocidal activity in both the repository and curative tests. The extract also prevented body weight loss and prolonged survival date of mice significantly (P < 0.05) at the highest dose employed in the study. Qualitative chemical assay for S. guineense methanolic leaf extract revealed that the plant is endowed with different plant secondary metabolites exemplified by terpenoids, alkaloids, triterpenes, flavonoids, anthraquinones, tannins, glycosides, saponins and phenols. Syzygium guineense leaf extract possess antimalarial activity in mice. The test substance was found to be safe with no observable signs of toxicity in the study mice. The results of the present work confirmed the in vitro antiplasmodial finding and traditional claims in vivo in mice. Therefore, Syzygium guineense could be regarded as a potential source to develop safe, effective and affordable antimalarial agent.

Anti-malarial activity and toxicity assessment of Himatanthus articulatus, a plant used to treat malaria in the Brazilian Amazon.

PubMed

Vale, Valdicley V; Vilhena, Thyago C; Trindade, Rafaela C Santos; Ferreira, Márlia Regina C; Percário, Sandro; Soares, Luciana F; Pereira, Washington Luiz A; Brandão, Geraldo C; Oliveira, Alaíde B; Dolabela, Maria F; De Vasconcelos, Flávio

2015-03-27

Plasmodium falciparum has become resistant to some of the available drugs. Several plant species are used for the treatment of malaria, such as Himatanthus articulatus in parts of Brazil. The present paper reports the phyto-chemistry, the anti-plasmodial and anti-malarial activity, as well as the toxicity of H. articulatus. Ethanol and dichloromethane extracts were obtained from the powder of stem barks of H. articulatus and later fractionated and analysed. The anti-plasmodial activity was assessed against a chloroquine resistant strain P. falciparum (W2) in vitro, whilst in vivo anti-malarial activity against Plasmodium berghei (ANKA strain) was tested in mice, evaluating the role of oxidative stress (total antioxidant capacity--TEAC; lipid peroxidation--TBARS, and nitrites and nitrates--NN). In addition, cytotoxicity was evaluated using the HepG2 A16 cell-line. The acute oral and sub-chronic toxicity of the ethanol extract were evaluated in both male and female mice. Plumieride was isolated from the ethyl acetate fraction of ethanol extract, Only the dichloromethane extract was active against clone W2. Nevertheless, both extracts reduced parasitaemia in P. berghei-infected mice. Besides, a significant reduction in pulmonary and cerebral levels of NN (nitrites and nitrates) was found, as well as in pulmonary TBARS, indicating a reduced oxidative damage to these organs. The ethanol extract showed low cytotoxicity to HepG2 A16 cells in the concentrations used. No significant changes were observed in the in vivo toxicity studies. The ethanol extract of H. articulatus proved to be promising as anti-malarial medicine and showed low toxicity.

Medicinal plants of the genus Anthocleista--A review of their ethnobotany, phytochemistry and pharmacology.

PubMed

Anyanwu, Gabriel O; Nisar-ur-Rehman; Onyeneke, Chukwu E; Rauf, Khalid

2015-12-04

The genus Anthocleista of the Gentianaceae family contains 14 species of trees and shrub-like plants distributed in tropical Africa, in Madagascar and on the Comoros. Traditionally, they are commonly used in the treatment of diabetes, hypertension, malaria, typhoid fever, obesity, diarrhea, dysentery, hyperprolactinemia, abdominal pain, ulcer, jaundice, asthma, hemorrhoids, hernia, cancer, wounds, chest pains, inflammations, rheumatism, STDs, infertility and skin diseases. They serve as an anthelmintic, laxative, diuretic and contraceptive. This review aims to provide for the first time a repository of ethnopharmacological information while critically evaluating the relation between the traditional medicinal uses, chemical constituents and pharmacological activities of the Anthocleista species so as to unveil opportunities for future research. A search for relevant information on Anthocleista species was performed on scientific databases (Pubmed, Google Scholar, SciFinder, Web of Science, Scopus, PubChem and other web sources such as The Plant List, Kew Botanical Garden and PROTA) and books, PhD and MSc dissertations for un-published resources. Out of the 14 species of Anthocleista, 6 have been reported in literature to be widely used in traditional medicine for the treatment of various ailments. The six species include: A. djalonensis, A. vogelii, A. nobilis, A. grandiflora, A. schweinfurthii, and A. liebrechtsiana. The chemical compounds isolated from Anthocleista species fall into the class of phytochemicals such as secoiridoids, nor-secoiridoids, xanthones, phytosterols, triterpenes, alkaloids, and others of which majority of the compounds were isolated from A. djalonensis and A. vogelii. The in vitro and in vivo pharmacological studies on the crude extracts, fractions and few isolated compounds of Anthocleista species showed antidiabetic, antiplasmodial, antimicrobial, hypotensive, spasmogenic, anti-obesity, antiulcerogenic, analgesic, anti-inflammatory, antioxidant, antitrypanosomal, anthelmintic, fertility, diuretic and laxative activities which supports most of their uses in traditional medicine. However, the bulk of the studies where centered on the antidiabetic, antiplasmodial and antimicrobial activities of Anthocleista species, although the evidence of its antiplasmodial effect was not convincing enough due to the discrepancies between the in vitro and in vivo results. A. djalonensis and A. vogelii are potential antidiabetic and antibacterial agents. The antibacterial potency relates to infections or diseases caused by E. coli, S. typhi and S. aureus such as urinary tract infections, typhoid, diarrhea, skin diseases, and food poisoning. Pharmacological research on this genus is quite elementary and limited, thus, more advanced research is necessary to isolate and determine the activities of bioactive compounds in vitro and in vivo, establish their mechanisms of action and commence the process of clinical research. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Bioorganometallic Chemistry and Malaria

NASA Astrophysics Data System (ADS)

Biot, Christophe; Dive, Daniel

This chapter summarizes recent developments in the design, synthesis, and structure-activity relationship studies of organometallic antimalarials. It begins with a general introduction to malaria and the biology of the parasite Plasmodium falciparum, with a focus on the heme detoxification system. Then, a number of metal complexes from the literature are reported for their antiplasmodial activity. The second half of the chapter deals with the serendipitous discovery of ferroquine, its mechanism(s) of action, and the failure to induce a resistance. Last, but not least, we suggest that the bioorganometallic approach offers the potential for the design of novel therapeutic agents.

Antimalarial efficacy of Albizia lebbeck (Leguminosae) against Plasmodium falciparum in vitro & P. berghei in vivo

PubMed Central

Kalia, Shagun; Walter, Neha Sylvia; Bagai, Upma

2015-01-01

Background & objectives: Albizia lebbeck Benth. (Leguminosae) has long been used in Indian traditional medicine. The current study was designed to test antimalarial activity of ethanolic bark extract of A. lebbeck (EBEAL). Methods: EBEAL was prepared by soxhlet extraction and subjected to phytochemical analysis. The extract was evaluated for its in vitro antimalarial activity against Plasmodium falciparum chloroquine (CQ) sensitive (MRC2) and CQ resistant (RKL9) strains. Cytotoxicity (CC50) of extract against HeLa cells was evaluated. Median lethal dose (LD50) was determined to assess safety of EBEAL in BALB/c mice. Schizonticidal (100-1000 mg/kg) and preventive (100-750 mg/kg) activities of EBEAL were evaluated against P. berghei. Curative activity (100-750 mg/kg) of extract was also evaluated. Results: Phytochemical screening revealed presence of alkaloids, flavonoids, phenols, saponins, terpenes and phytosterols. The extract exhibited IC50 of 8.2 μg/ml (MRC2) and 5.1 μg/ml (RKL9). CC50 of extract on HeLa cell line was calculated to be >1000 μg/ml. EBEAL showed selectivity indices (SI) of >121.9 and >196.07 against MRC2 and RKL9 strains of P. falciparum, respectively. LD50 of EBEAL was observed to be >5 g/kg. Dose-dependent chemosuppression was observed with significant (P<0.001) schizonticidal activity at 1000 mg/kg with ED50 >100 mg/kg. Significant (P<0.001) curative and repository activities were exhibited by 750 mg/kg concentration of extract on D7. Interpretation & conclusions: The present investigation reports antiplasmodial efficacy of EBEAL in vitro against P. falciparum as evident by high SI values. ED50 of <100 mg/kg against P. berghei categorizes EBEAL as active antimalarial. Further studies need to be done to exploit its antiplasmodial activity further. PMID:26905234

Extracts Obtained from Pterocarpus angolensis DC and Ziziphus mucronata Exhibit Antiplasmodial Activity and Inhibit Heat Shock Protein 70 (Hsp70) Function.

PubMed

Zininga, Tawanda; Anokwuru, Chinedu P; Sigidi, Muendi T; Tshisikhawe, Milingoni P; Ramaite, Isaiah I D; Traoré, Afsatou N; Hoppe, Heinrich; Shonhai, Addmore; Potgieter, Natasha

2017-07-28

Malaria parasites are increasingly becoming resistant to currently used antimalarial therapies, therefore there is an urgent need to expand the arsenal of alternative antimalarial drugs. In addition, it is also important to identify novel antimalarial drug targets. In the current study, extracts of two plants, Pterocarpus angolensis and Ziziphus mucronata were obtained and their antimalarial functions were investigated. Furthermore, we explored the capability of the extracts to inhibit Plasmodium falciparum heat shock protein 70 (Hsp70) function. Heat shock protein 70 (Hsp70) are molecular chaperones whose function is to facilitate protein folding. Plasmodium falciparum the main agent of malaria, expresses two cytosol-localized Hsp70s: PfHsp70-1 and PfHsp70-z. The PfHsp70-z has been reported to be essential for parasite survival, while inhibition of PfHsp70-1 function leads to parasite death. Hence both PfHsp70-1 and PfHsp70-z are potential antimalarial drug targets. Extracts of P. angolensis and Z. mucronata inhibited the basal ATPase and chaperone functions of the two parasite Hsp70s. Furthermore, fractions of P. angolensis and Z. mucronata inhibited P. falciparum 3D7 parasite growth in vitro. The extracts obtained in the current study exhibited antiplasmodial activity as they killed P. falciparum parasites maintained in vitro. In addition, the findings further suggest that some of the compounds in P. angolensis and Z. mucronata may target parasite Hsp70 function.

Additive In Vitro Antiplasmodial Effect of N-Alkyl and N-Benzyl-1,10-Phenanthroline Derivatives and Cysteine Protease Inhibitor E64

PubMed Central

Wijayanti, Mahardika Agus; Sholikhah, Eti Nurwening; Hadanu, Ruslin; Jumina, Jumina; Supargiyono, Supargiyono; Mustofa, Mustofa

2010-01-01

Potential new targets for antimalarial chemotherapy include parasite proteases, which are required for several cellular functions during the Plasmodium falciparum life cycle. Four new derivatives of N-alkyl and N-benzyl-1,10-phenanthroline have been synthesized. Those are (1)-N-methyl-1,10-phenanthrolinium sulfate, (1)-N-ethyl-1,10-phenanthrolinium sulfate, (1)-N-benzyl-1,10-phenanthrolinium chloride, and (1)-N-benzyl-1,10-phenanthrolinium iodide. Those compounds had potential antiplasmodial activity with IC50 values from 260.42 to 465.38 nM. Cysteine proteinase inhibitor E64 was used to investigate the mechanism of action of N-alkyl and N-benzyl-1,10-phenanthroline derivatives. A modified fixed-ratio isobologram method was used to study the in vitro interactions between the new compounds with either E64 or chloroquine. The interaction between N-alkyl and N-benzyl-1,10-phenanthroline derivatives and E64 was additive as well as their interactions with chloroquine were also additive. Antimalarial mechanism of chloroquine is mainly on the inhibition of hemozoin formation. As the interaction of chloroquine and E64 was additive, the results indicated that these new compounds had a mechanism of action by inhibiting Plasmodium proteases. PMID:22332022

New pentasubstituted pyrrole hybrid atorvastatin-quinoline derivatives with antiplasmodial activity.

PubMed

Carvalho, Rita C C; Martins, Wagner A; Silva, Tayara P; Kaiser, Carlos R; Bastos, Mônica M; Pinheiro, Luiz C S; Krettli, Antoniana U; Boechat, Núbia

2016-04-15

Cerebral malaria is caused by Plasmodium falciparum. Atorvastatin (AVA) is a pentasubstituted pyrrole, which has been tested as an adjuvant in the treatment of cerebral malaria. Herein, a new class of hybrids of AVA and aminoquinolines (primaquine and chloroquine derivatives) has been synthesized. The quinolinic moiety was connected to the pentasubstituted pyrrole from AVA by a linker group (CH2)n=2-4 units. The activity of the compounds increased with the size of the carbons chain. Compound with n=4 and 7-chloroquinolinyl has displayed better activity (IC50=0.40 μM) than chloroquine. The primaquine derivative showed IC50=1.41 μM, being less toxic and more active than primaquine. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antimalarial activity of abietane ferruginol analogues possessing a phthalimide group.

PubMed

González, Miguel A; Clark, Julie; Connelly, Michele; Rivas, Fatima

2014-11-15

The abietane-type diterpenoid (+)-ferruginol, a bioactive compound isolated from New Zealand's Miro tree (Podocarpus ferruginea), displays relevant pharmacological properties, including antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and anticancer. Herein, we demonstrate that ferruginol (1) and some phthalimide containing analogues 2-12 have potential antimalarial activity. The compounds were evaluated against malaria strains 3D7 and K1, and cytotoxicity was measured against a mammalian cell line panel. A promising lead, compound 3, showed potent activity with an EC50 = 86 nM (3D7 strain), 201 nM (K1 strain) and low cytotoxicity in mammalian cells (SI>290). Some structure-activity relationships have been identified for the antimalarial activity in these abietane analogues. Copyright © 2014 Elsevier Ltd. All rights reserved.

Antiplasmodial activity of novel keto-enamine chalcone-chloroquine based hybrid pharmacophores.

PubMed

Sashidhara, Koneni V; Kumar, Manoj; Modukuri, Ram K; Srivastava, Rajeev Kumar; Soni, Awakash; Srivastava, Kumkum; Singh, Shiv Vardan; Saxena, J K; Gauniyal, Harsh M; Puri, Sunil K

2012-05-01

A series of novel keto-enamine chalcone-chloroquine based hybrids were synthesized following new methodology developed in our laboratory. The synthesized compounds were screened against chloroquine sensitive strain (3D7) of Plasmodium falciparum in an in vitro model. Some of the compounds were showing comparable antimalarial activity at par with chloroquine. Compounds with significant in vitro antimalarial activity were then evaluated for their in vivo efficacy in Swiss mice against Plasmodium yoelii (chloroquine resistant N-67 strain), wherein compounds 25 and 27 each showed an in vivo suppression of 99.9% parasitaemia on day 4. Biochemical studies reveal that inhibition of hemozoin formation is the primary mechanism of action of these analogues. Copyright © 2012 Elsevier Ltd. All rights reserved.

Metallocene-based antimalarials: an exploration into the influence of the ferrocenyl moiety on in vitro antimalarial activity in chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum.

PubMed

Blackie, Margaret A L; Beagley, Paul; Croft, Simon L; Kendrick, Howard; Moss, John R; Chibale, Kelly

2007-10-15

To establish the role of the ferrocenyl moiety in the antiplasmodial activity of ferroquine, compounds in which this moiety is replaced by the corresponding ruthenium-based moieties were synthesized and evaluated. In both the sensitive (D10) and resistant (K1) strains of Plasmodium falciparum, ruthenoquine analogues showed comparable potency to ferroquine. This suggests that a probable role of the ferrocenyl fragment is to serve simply as a hydrophobic spacer group. In addition, ferroquine analogues with different aromatic substituents were synthesized and evaluated. Unexpectedly high activity for quinoline compounds lacking the 7-chloro substituent suggests the ferrocenyl moiety may have an additive and/or synergistic effect.

Screening and HPLC-Based Activity Profiling for New Antiprotozoal Leads from European Plants.

PubMed

Zimmermann, Stefanie; Thomi, Semira; Kaiser, Marcel; Hamburger, Matthias; Adams, Michael

2012-01-01

Based on a survey of remedies used in Renaissance Europe to treat malaria, we prepared and screened a library of 254 extracts from 61 plants for antiplasmodial activity in vitro. HPLC-based activity profiling was performed for targeted identification of active constituents in extracts. One of the most remarkable results was the identification of onopordopicrin, a germacranolide sesquiterpene lactone isolated from Arctium nemorosum as a potent inhibitor of P. falciparum with an IC(50) of 6.9 μM. It was tested similarly against Trypanosoma brucei rhodesiense, the parasite which causes African sleeping sickness. With an IC(50) of 0.37 μM, onopordopicrin was one of the most potent natural products reported so far. Cytotoxicity was determined against rat myoblast L6 cells (IC(50): 3.06).

Screening and HPLC-Based Activity Profiling for New Antiprotozoal Leads from European Plants

PubMed Central

Zimmermann, Stefanie; Thomi, Semira; Kaiser, Marcel; Hamburger, Matthias; Adams, Michael

2012-01-01

Based on a survey of remedies used in Renaissance Europe to treat malaria, we prepared and screened a library of 254 extracts from 61 plants for antiplasmodial activity in vitro. HPLC-based activity profiling was performed for targeted identification of active constituents in extracts. One of the most remarkable results was the identification of onopordopicrin, a germacranolide sesquiterpene lactone isolated from Arctium nemorosum as a potent inhibitor of P. falciparum with an IC50 of 6.9 μM. It was tested similarly against Trypanosoma brucei rhodesiense, the parasite which causes African sleeping sickness. With an IC50 of 0.37 μM, onopordopicrin was one of the most potent natural products reported so far. Cytotoxicity was determined against rat myoblast L6 cells (IC50: 3.06). PMID:22396915

Two novel assays for the detection of haemin-binding properties of antimalarials evaluated with compounds isolated from medicinal plants.

PubMed

Steele, J C P; Phelps, R J; Simmonds, M S J; Warhurst, D C; Meyer, D J

2002-07-01

Forty-two compounds isolated from nine plants used within South America for the treatment of malaria were tested for haemin binding using two novel, rapid screening methods. The data obtained were analysed with respect to IC(50) values for in vitro toxicity to Plasmodium falciparum trophozoites. One method, a multiwell assay based on the inhibition of the interaction of haemin with glutathione (GSH), is sensitive in the 10 microM range, takes c. 1 h and is suitable for either a high throughput screen or rapid assay during natural product isolation. Of 19 compounds showing antiplasmodial activity (IC(50) < 40 microM), 16 (84%) showed >40% inhibition of GSH-haemin reaction. The sensitivity and specificity of the assay were 0.85 and 0.82, respectively. The positive predictive value was 0.81 and the negative predictive value 0.86. A more sensitive assay (0.1 microM range) is based on the reversal by haemin-binding compounds of the haemin inhibition of the L-dopachrome-methyl ester tautomerase activity of human macrophage migration inhibitory factor. This assay gives a better idea of the affinity of interaction and uses very small amounts of test compound. The log[RI(50)] of eight of the compounds that tested positive in the above assays together with those of quinine and chloroquine showed a positive correlation with log[antiplasmodial IC(50)] for strain T9-96 (r = 0.824) and strain K1 (r = 0.904). Several of the antimalarial compounds that bind haemin are isoquinolines, a class not shown previously to interact with haemin.

Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions

PubMed Central

2011-01-01

Background In traditional medicine whole plants or mixtures of plants are used rather than isolated compounds. There is evidence that crude plant extracts often have greater in vitro or/and in vivo antiplasmodial activity than isolated constituents at an equivalent dose. The aim of this paper is to review positive interactions between components of whole plant extracts, which may explain this. Methods Narrative review. Results There is evidence for several different types of positive interactions between different components of medicinal plants used in the treatment of malaria. Pharmacodynamic synergy has been demonstrated between the Cinchona alkaloids and between various plant extracts traditionally combined. Pharmacokinetic interactions occur, for example between constituents of Artemisia annua tea so that its artemisinin is more rapidly absorbed than the pure drug. Some plant extracts may have an immunomodulatory effect as well as a direct antiplasmodial effect. Several extracts contain multidrug resistance inhibitors, although none of these has been tested clinically in malaria. Some plant constituents are added mainly to attenuate the side-effects of others, for example ginger to prevent nausea. Conclusions More clinical research is needed on all types of interaction between plant constituents. This could include clinical trials of combinations of pure compounds (such as artemisinin + curcumin + piperine) and of combinations of herbal remedies (such as Artemisia annua leaves + Curcuma longa root + Piper nigum seeds). The former may enhance the activity of existing pharmaceutical preparations, and the latter may improve the effectiveness of existing herbal remedies for use in remote areas where modern drugs are unavailable. PMID:21411015

Ceanothane-type triterpenoids from Cyphostemma adenocaule.

PubMed

Chouna, Jean Rodolphe; Nardella, Flore; Lenta, Bruno Ndjakou; Vonthron-Sénécheau, Catherine; Nkeng-Efouet-Alango, Pépin; Sewald, Norbert

2016-07-26

Phytochemical investigation of the methanol extract of Cyphostemma adenocaule liana (bark and wood) led to the isolation of two new ceanothane-type triterpenoids, cyphostemmic acid A 1 and cyphostemmic acid B 2, together with the known triterpenoids 3-7, β-sitosterol and its glucoside. The structures of the isolated compounds were established by 1D- and 2D-NMR spectroscopy. Ozonolysis of cyphostemmic acid A 1, epigouanic acid A 3 and betulin 6 yielded semisynthetic derivatives, cyphostemmic acid C 8, cyphostemmic acid D 9, and 3β,28-dihydroxy-30-norlupan-20-one 10 respectively. Compounds 1-4, 6, 8-10 were tested in vitro, for their antiplasmodial activity against Plasmodium falciparum 3D7 strain and showed weak activity.

A natural product based DOS library of hybrid systems.

PubMed

Prabhu, Ganesh; Agarwal, Shalini; Sharma, Vijeta; Madurkar, Sanjay M; Munshi, Parthapratim; Singh, Shailja; Sen, Subhabrata

2015-05-05

Here we described a natural product inspired modular DOS strategy for the synthesis of a library of hybrid systems that are structurally and stereochemically disparate. The main scaffold is a pyrroloisoquinoline motif, that is synthesized from tandem Pictet-Spengler lactamization. The structural diversity is generated via "privileged scaffolds" that are attached at the appropriate site of the motif. Screening of the library compounds for their antiplasmodial activity against chloroquine sensitive 3D7 cells indicated few compounds with moderate activity (20-50 μM). A systematic comparison of structural intricacy between the library members and a natural product dataset obtained from ZINC(®) revealed comparable complexity. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Medicinal plants used for management of malaria among the Luhya community of Kakamega East sub-County, Kenya.

PubMed

Mukungu, Nillian; Abuga, Kennedy; Okalebo, Faith; Ingwela, Raphael; Mwangi, Julius

2016-12-24

Malaria remains a major health problem worldwide especially in sub-Saharan Africa. In Kenya, 80% of the population is at risk of contracting the disease. Pregnant mothers and children under five years are the most affected by this disease. Antimalarial drug resistance poses a major threat in the fight against malaria necessitating continuous search for new antimalarial drugs. Due to inadequate and inaccessible health facilities, majority of people living in rural communities heavily depend on traditional medicine which involves the use of medicinal plants for the management of malaria. Most of these indigenous knowledge is undocumented and risks being lost yet such information could be useful in the search of new antimalarial agents. An ethnobotanical survey was carried out among the Luhya community of Kakamega East sub-County, a malaria epidemic region, with the aim of documenting the plants used in the management of malaria. Semi-structured questionnaires were used to collect information from 21 informants who included traditional medicine practitioners and other caregivers who had experience in use of plants in management of malaria. These were drawn from 4 villages located in Kakamega East sub-county, within Kakamega County based on their differences in topography. Information recorded included plant names, parts used, mode of preparation and administration and the sources of plant materials. A literature search was conducted using PubMed and google scholar to identify the reported traditional uses of these plants and studied antiplasmodial activities. In this study, 57% of the informants were aged above 50 years and a total of 61% had either no formal education or had only attained primary school education. A total of 42 plant species belonging to 24 families were identified. Most plants used in the management of malaria in this community belonged to Lamiaceae (18%), Leguminosae (9%) and Compositae (9%) plant families. Plants mostly used included Melia azedarach L, Aloe spp, Ajuga integrifolia Buch. Ham, Vernonia amygdalina Del., Rotheca myricoides (Hochst.) Steane and Mabb, Fuerstia africana T.C.E.Fr., Zanthoxylum gilletii (De Wild.) P.G.Waterman and Leucas calostachys Oliv. Rumex steudelii Hochst.ex A. Rich and Phyllanthus sepialis Müll. Arg are reported for the first time in the management of malaria. Although Clerodendrum johnstonii Oliv. (Jeruto et al., 2011) and Physalis peruviana L.(Ramadan et al., 2015) are reported in other studies for management of malaria, no studies have been carried out to demonstrate their antiplasmodial activity. The plant parts mostly used were the leaves (36%) and stem barks (26%). Majority of these plants were prepared as decoctions by boiling and allowed to cool before administration (66%) while infusions accounted for 28% of the preparations. The literature mined supports the use of these plants for the management of malaria since most of them have demonstrated in-vitro and in-vivo antiplasmodial activities. Most of the reported plant species in this study have been investigated for antiplasmodial activity and are in agreement with the ethnomedical use. Two (2) plants are reported for the first time in the management of malaria. There is need for documentation and preservation of the rich ethnomedical knowledge within this community given that most of the practitioners are advanced in age and less educated. There is also the danger of over-exploitation of plant species as most of them are obtained from the wild, mainly Kakamega forest. Therefore, there is need for determining the economically and medicinally important plants in this community and planning for their preservation. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

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

PubMed

Wulandari, Diah Anggraini; Sidhartha, Elizabeth; Setyaningsih, Iriani; Marbun, Jonathan Marshall; Syafruddin, Din; Asih, Puji Budi Setia

2017-08-02

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 (IC 50  = 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.

In Vitro Activity of wALADin Benzimidazoles against Different Life Cycle Stages of Plasmodium Parasites

PubMed Central

Lentz, Christian S.; Sattler, Julia M.; Fendler, Martina; Gottwalt, Simon; Halls, Victoria S.; Strassel, Silke; Arriens, Sandra; Hannam, Jeffrey S.; Specht, Sabine; Famulok, Michael; Mueller, Ann-Kristin; Hoerauf, Achim

2014-01-01

wALADin1 benzimidazoles are specific inhibitors of δ-aminolevulinic acid dehydratase from Wolbachia endobacteria of filarial nematodes. We report that wALADin1 and two derivatives killed blood stage Plasmodium falciparum in vitro (50% inhibitory concentrations, 39, 7.7, and 12.8 μM, respectively). One of these derivatives inhibited gliding motility of Plasmodium berghei ANKA infectious sporozoites with nanomolar affinity and blocked invasion into hepatocytes but did not affect intrahepatocytic replication. Hence, wALADin1 benzimidazoles are tools to study gliding motility and potential antiplasmodial drug candidates. PMID:25313210

Treatment of malaria and related symptoms using traditional herbal medicine in Ethiopia.

PubMed

Suleman, Sultan; Beyene Tufa, Takele; Kebebe, Dereje; Belew, Sileshi; Mekonnen, Yimer; Gashe, Fanta; Mussa, Seid; Wynendaele, Evelien; Duchateau, Luc; De Spiegeleer, Bart

2018-03-01

Medicinal plants have always been an integral part of different cultures in Ethiopia in the treatment of different illnesses including malaria and related symptoms. However, due to lack of proper documentation, urbanization, drought, acculturation and deforestation, there is an increased risk of losing this traditional knowledge. Hence, the use of the indigenous knowledge should be well documented and validated for potential future use. To gather and document information on medicinal plants which are used in the traditional treatment of malaria and related symptoms in Ethiopia. First, an ethnomedicinal survey of plants was conducted in 17 districts of Jimma zone, the Oromia national regional state of Ethiopia. Jimma zone is malarious and rich in natural flora. A total of 115 traditional healers were interviewed using a semi-structured questionnaire containing personal data of the respondents, and information on medicinal plants used to treat malaria and related symptoms. In addition, a literature search using Medline/PubMed, Google Scholar, ScienceDirect and HINARI was conducted on the indigenous use, in-vitro/in-vivo anti-malarial activity reports, and the chemical characterization of medicinal plants of Ethiopia used against malaria. From ethnomedicinal survey, a total of 28 species of plants used in the traditional treatment of malaria and related symptoms in Jimma Zone were collected, identified and documented. In addition, the literature search revealed that 124 medicinal plant species were reported to be traditionally used in the treatment of malaria in Ethiopia. From both ethnomedicinal survey and the literature search, Asteraceae and Fabaceae were the most represented families and Allium sativum L., Carica papaya L., Vernonia amygdalina Del., Lepidium sativum L. and Croton macrostachyus Del. were the most frequently reported plant species for their anti-malarial use. The dominant plant parts used in the preparation of remedies were leaves. About 54% of the medicinal plants documented in the survey have been reported as an anti-malarial plant in the literature search. Furthermore, the in-vitro and in-vivo anti-plasmodial activity reports of extracts from some of plant species were found to support the traditional claim of the documented plants. Moreover, literatures indicate that several secondary metabolites isolated from certain plant species that are traditionally used for the treatment of malaria and related symptoms in Ethiopia demonstrate strong anti-plasmodial activity. The result of the current study showed that traditional knowledge is still playing an important role in the management of malaria and related symptoms in Ethiopia. Allium sativum L., Carica papaya L., Vernonia amygdalina Del., and Lepidium sativum L. are the most commonly reported species as anti-malarial plants and the traditional claim of some species was supported by known anti-plasmodial activity and bioactivity reports. The finding of this study is important in the rational prioritization of plant species which are potentially used for investigating new compounds, which could be efficacious for malaria treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Antimalarial Activities of Peptide Antibiotics Isolated from Fungi

PubMed Central

Nagaraj, G.; Uma, M. V.; Shivayogi, M. S.; Balaram, Hemalatha

2001-01-01

Malaria caused by Plasmodium falciparum is a major public health problem in the developing countries of the world. Clinical treatment of malaria has become complicated due to the occurrence of infections caused by drug resistant parasites. Secondary metabolites from fungi are an attractive source of chemotherapeutic agents. This work reports the isolation and in vitro antiplasmodial activities of peptide antibiotics of fungal origin. The three peptide antibiotics used in this study were efrapeptins, zervamicins, and antiamoebin. The high-performance liquid chromatography-purified peptides were characterized by nuclear magnetic resonance and mass spectral analysis. All three fungal peptides kill P. falciparum in culture with 50% inhibitory concentrations in the micromolar range. A possible mode of action of these peptide antibiotics on P. falciparum is presented. PMID:11120957

A Review on Ethnopharmacological Applications, Pharmacological Activities, and Bioactive Compounds of Mangifera indica (Mango)

PubMed Central

2017-01-01

Mangifera indica (family Anacardiaceae), commonly known as mango, is a pharmacologically, ethnomedically, and phytochemically diverse plant. Various parts of M. indica tree have been used in traditional medicine for the treatment of different ailments, and a number of bioactive phytochemical constituents of M. indica have been reported, namely, polyphenols, terpenes, sterols, carotenoids, vitamins, and amino acids, and so forth. Several studies have proven the pharmacological potential of different parts of mango trees such as leaves, bark, fruit peel and flesh, roots, and flowers as anticancer, anti-inflammatory, antidiabetic, antioxidant, antibacterial, antifungal, anthelmintic, gastroprotective, hepatoprotective, immunomodulatory, antiplasmodial, and antihyperlipemic. In the present review, a comprehensive study on ethnopharmacological applications, pharmacological activities, and bioactive compounds of M. indica has been described. PMID:29456572

A phenolic glycoside from Flacourtia indica induces heme mediated oxidative stress in Plasmodium falciparum and attenuates malaria pathogenesis in mice.

PubMed

Singh, Shiv Vardan; Manhas, Ashan; Singh, Suriya P; Mishra, Sonali; Tiwari, Nimisha; Kumar, Parmanand; Shanker, Karuna; Srivastava, Kumkum; Sashidhara, Koneni V; Pal, Anirban

2017-07-01

Flacourtia indica is especially popular among the various communities of many African countries where it is being used traditionally for the treatment of malaria. In our previous report, we have identified some phenolic glycosides from the aerial parts of F. indica as promising antiplasmodial agents under in vitro conditions. Antimalarial bioprospection of F. indica derived phenolic glycoside in Swiss mice (in vivo) with special emphasis on its mode of action. Chloroquine sensitive strain of Plasmodium falciparum was routinely cultured and used for the in vitro studies. The in vivo antimalarial potential of phenolic glycoside was evaluated against P. berghei in Swiss mice through an array of parameters viz., hematological, biochemical, chemo-suppression and mean survival time. 2-(6-benzoyl-β-d-glucopyranosyloxy)-7-(1α, 2α, 6α-trihydroxy-3-oxocyclohex-4-enoyl)-5-hydroxybenzyl alcohol (CPG), a phenolic glycoside isolated from the aerial parts of F. indica was found to exhibit promising antiplasmodial activity by arresting the P. falciparum growth at the trophozoite stage. Spectroscopic investigations reveal that CPG possesses a strong binding affinity with free heme moieties. In addition, these interactions lead to the inhibition of heme polymerization in malaria parasite, augmenting oxidative stress, and delaying the rapid growth of parasite. Under in-vivo condition, CPG exhibited significant antimalarial activity against P. berghei at 50 and 75mg/kg body weight through chemo-suppression of parasitemia and ameliorating the parasite induced inflammatory and oxidative (hepatic) imbalance in the experimental mice. CPG was found to be a potential antimalarial constituent of F. indica with an explored mechanism of action, which also offers the editing choices for developing CPG based antimalarial chemotypes. Copyright © 2017 Elsevier GmbH. All rights reserved.

Anti-malarial property of steroidal alkaloid conessine isolated from the bark of Holarrhena antidysenterica.

PubMed

Dua, Virendra K; Verma, Gaurav; Singh, Bikram; Rajan, Aswathy; Bagai, Upma; Agarwal, Dau Dayal; Gupta, N C; Kumar, Sandeep; Rastogi, Ayushi

2013-06-10

In the face of chronic and emerging resistance of parasites to currently available drugs and constant need for new anti-malarials, natural plant products have been the bastion of anti-malarials for thousands of years. Moreover natural plant products and their derivatives have traditionally been a common source of drugs, and represent more than 30% of the current pharmaceutical market. The present study shows evaluation of anti-malarial effects of compound conessine isolated from plant Holarrhena antidysenterica frequently used against malaria in the Garhwal region of north-west Himalaya. In vitro anti-plasmodial activity of compound was assessed using schizont maturation and parasite lactate dehydrogenase (pLDH) assay. Cytotoxic activities of the examined compound were determined on L-6 cells of rat skeletal muscle myoblast. The four-day test for anti-malarial activity against a chloroquine-sensitive Plasmodium berghei NK65 strain in BALB/c mice was used for monitoring in vivo activity of compound. In liver and kidney function test, the activity of alkaline phosphatase (ALP) was examined by p-NPP method, bilirubin by Jendrassik and Grof method. The urea percentage was determined by modified Berthelot method and creatinine by alkaline picrate method in serum of mice using ENZOPAK/CHEMPAK reagent kits. Compound conessine showed in vitro anti-plasmodial activity with its IC₅₀ value 1.9 μg/ml and 1.3 μg/ml using schizont maturation and pLDH assay respectively. The compound showed cytotoxity IC₅₀= 14 μg/ml against L6 cells of rat skeletal muscle myoblast. The isolated compound from plant H. antidysenterica significantly reduced parasitaemia (at 10 mg/kg exhibited 88.95% parasite inhibition) in P. berghei-infected mice. Due to slightly toxic nature (cytotoxicity = 14), biochemical analysis (liver and kidney function test) of the serum from mice after administration of conessine were also observed. The present investigation demonstrates that the compound conessine exhibited substantial anti-malarial property. The isolated compound could be chemically modified to obtain a more potent chemical entity with improved characteristics against malaria.

In vitro activity of wALADin benzimidazoles against different life cycle stages of Plasmodium parasites.

PubMed

Lentz, Christian S; Sattler, Julia M; Fendler, Martina; Gottwalt, Simon; Halls, Victoria S; Strassel, Silke; Arriens, Sandra; Hannam, Jeffrey S; Specht, Sabine; Famulok, Michael; Mueller, Ann-Kristin; Hoerauf, Achim; Pfarr, Kenneth M

2015-01-01

wALADin1 benzimidazoles are specific inhibitors of δ-aminolevulinic acid dehydratase from Wolbachia endobacteria of filarial nematodes. We report that wALADin1 and two derivatives killed blood stage Plasmodium falciparum in vitro (50% inhibitory concentrations, 39, 7.7, and 12.8 μM, respectively). One of these derivatives inhibited gliding motility of Plasmodium berghei ANKA infectious sporozoites with nanomolar affinity and blocked invasion into hepatocytes but did not affect intrahepatocytic replication. Hence, wALADin1 benzimidazoles are tools to study gliding motility and potential antiplasmodial drug candidates. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Synthesis and antimalarial activity of new 4-amino-7-chloroquinolyl amides, sulfonamides, ureas and thioureas.

PubMed

Ekoue-Kovi, Kekeli; Yearick, Kimberly; Iwaniuk, Daniel P; Natarajan, Jayakumar K; Alumasa, John; de Dios, Angel C; Roepe, Paul D; Wolf, Christian

2009-01-01

We report the synthesis and in vitro antimalarial activities of more than 50 7-chloro-4-aminoquinolyl-derived sulfonamides 3-8 and 11-26, ureas 19-22, thioureas 23-26, and amides 27-54. Many of the CQ analogues prepared for this study showed submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strains of Plasmodium falciparum) and low resistance indices were obtained in most cases. Systematic variation of the side chain length and introduction of fluorinated aliphatic and aromatic termini revealed promising leads that overcome CQ resistance. In particular, sulfonamide 3 exhibiting a short side chain with a terminal dansyl moiety combined high antiplasmodial potency with a low resistance index and showed IC(50)s of 17.5 and 22.7 nM against HB3 and Dd2 parasites.

Design, Synthesis, and Biological Evaluation of Peptidomimetic N-Substituted Cbz-4-Hyp-Hpa-Amides as Novel Inhibitors of Plasmodium falciparum.

PubMed

Bacherikov, Valeriy A; Chittiboyina, Amar G; Avery, Mitchell A

2017-08-01

A new series of peptidomimetic N-substituted Cbz-4-Hyp-Hpa-amides were designed, synthesized, and evaluated for inhibition of the Plasmodium falciparum. Substituents on the N-atom of the amide group were selected alkyl-, allyl-, aryl-, 2-hydroxyethyl-, 2-cyanoethyl-, cyanomethyl-, 2-hydroxyethyl-, 2,2-diethoxyethyl-, or 2-ethoxy-2-oxoethylamino groups, and about of 40 new compounds were synthesized and evaluated for antiplasmodial activity in vitro. Antimalarial activity has been investigated as for the final peptide mimetics, and their immediate predecessors, carrying TBDMS or TBDPS protecting groups on 4-hydroxyproline residue and 18 derivatives exhibited toxicity against P. falciparum. Of these agents, compound 23e was shown to have potent antimalarial activity with IC 50 528 ng/ml. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

Identification of β-Amino alcohol grafted 1,4,5 trisubstituted 1,2,3-triazoles as potent antimalarial agents.

PubMed

Devender, Nalmala; Gunjan, Sarika; Chhabra, Stuti; Singh, Kartikey; Pasam, Venkata Reddy; Shukla, Sanjeev K; Sharma, Abhisheak; Jaiswal, Swati; Singh, Sunil Kumar; Kumar, Yogesh; Lal, Jawahar; Trivedi, Arun Kumar; Tripathi, Renu; Tripathi, Rama Pati

2016-02-15

In a quest to discover new drugs, we have synthesized a series of novel β-amino alcohol grafted 1,2,3-triazoles and screened them for their in vitro antiplasmodial and in vivo antimalarial activity. Among them, compounds 16 and 25 showed potent activity against chloroquine-sensitive (Pf3D7) strain with IC50 of 0.87 and 0.3 μM respectively, while compounds 7 and 13 exhibited better activity in vitro than the reference drug against chloroquine-resistance strain (PfK1) with IC50 of 0.5 μM each. Compound 25 showed 86.8% in vivo antimalarial efficacy with favorable pharmacokinetic parameters. Mechanistic studies divulged that potent compounds significantly boosted p53 protein levels to exhibit the antimalarial activity. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Bioisosteric ferrocenyl-containing quinolines with antiplasmodial and antitrichomonal properties

USDA-ARS?s Scientific Manuscript database

A series of ferrocenyl'containing quinolines and ferrocenylamines were prepared and fully characterized. The molecular structures of two ferrocenyl'containing quinolines, determined using single'crystal x'ray diffraction, revealed that the compounds crystallise in a folded conformation. The compound...

The potential of anti-malarial compounds derived from African medicinal plants, part II: a pharmacological evaluation of non-alkaloids and non-terpenoids

PubMed Central

2014-01-01

Malaria is currently a public health concern in many countries in the world due to various factors which are not yet under check. Drug discovery projects targeting malaria often resort to natural sources in the search for lead compounds. A survey of the literature has led to a summary of the major findings regarding plant-derived compounds from African flora, which have shown anti-malarial/antiplasmodial activities, tested by in vitro and in vivo assays. Considerations have been given to compounds with activities ranging from “very active” to “weakly active”, leading to >500 chemical structures, mainly alkaloids, terpenoids, flavonoids, coumarins, phenolics, polyacetylenes, xanthones, quinones, steroids and lignans. However, only the compounds that showed anti-malarial activity, from “very active” to “moderately active”, are discussed in this review. PMID:24602358

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

PubMed

Soares, Roberta Reis; da Silva, José Marcio Fernandes; Carlos, Bianca Cecheto; da Fonseca, Camila Campos; de Souza, Laila Salomé Araújo; Lopes, Fernanda Valério; de Paula Dias, Rafael Mafra; Moreira, Paulo Otávio Lourenço; Abramo, Clarice; Viana, Gustavo Henrique Ribeiro; de Pila Varotti, Fernando; da Silva, Adilson David; Scopel, Kézia Katiani Gorza

2015-06-01

Malaria continues to be an important public health problem in the world. Nowadays, the widespread parasite resistance to many drugs used in antimalarial therapy has made the effective treatment of cases and control of the disease a constant challenge. Therefore, the discovery of new molecules with good antimalarial activity and tolerance to human use can be really important in the further treatment of the disease. In this study we have investigated the antiplasmodial activity of 10 synthetic compounds derived from quinoline, five of them combined to sulfonamide and five to the hydrazine or hydrazide group. The compounds were evaluated according to their cytotoxicity against HepG2 and HeLa cell lines, their antimalarial activity against CQ-sensitive and CQ-resistant Plasmodium falciparum strains and, finally, their schizonticide blood action in mice infected with Plasmodium berghei NK65. The compounds exhibited no cytotoxic action in HepG2 and HeLa cell lines when tested up to a concentration of 100 μg/mL. In addition, the hydrazine or hydrazide derivative compounds were less cytotoxic against cell lines and more active against CQ-sensitive and CQ-resistant P. falciparum strains, showing high SI (>1000 when SI was calculated using the CC50 from the 3D7 strain as reference). When tested in vivo, the hydrazine derivative 1f compound showed activity against the development of blood parasites similar to that observed with CQ, the reference drug. Interestingly, the 1f compound demonstrated the best LipE value (4.84) among all those tested in vivo. Considering the in vitro and in vivo activities of the compounds studied here and the LipE values, we believe the 1f compound to be the most promising molecule for further studies in antimalarial chemotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Thiopeptide Antibiotics: Retrospective and Recent Advances

PubMed Central

Just-Baringo, Xavier; Albericio, Fernando; Álvarez, Mercedes

2014-01-01

Thiopeptides, or thiazolyl peptides, are a relatively new family of antibiotics that already counts with more than one hundred different entities. Although they are mainly isolated from soil bacteria, during the last decade, new members have been isolated from marine samples. Far from being limited to their innate antibacterial activity, thiopeptides have been found to possess a wide range of biological properties, including anticancer, antiplasmodial, immunosuppressive, etc. In spite of their ribosomal origin, these highly posttranslationally processed peptides have posed a fascinating synthetic challenge, prompting the development of various methodologies and strategies. Regardless of their limited solubility, intensive investigations are bringing thiopeptide derivatives closer to the clinic, where they are likely to show their veritable therapeutic potential. PMID:24445304

In vitro studies on the sensitivity pattern of Plasmodium falciparum to anti-malarial drugs and local herbal extracts.

PubMed

Olasehinde, Grace I; Ojurongbe, Olusola; Adeyeba, Adegboyega O; Fagade, Obasola E; Valecha, Neena; Ayanda, Isaac O; Ajayi, Adesola A; Egwari, Louis O

2014-02-20

The resistance of human malaria parasites to anti-malarial compounds has become considerable concern, particularly in view of the shortage of novel classes of anti-malarial drugs. One way to prevent resistance is by using new compounds that are not based on existing synthetic antimicrobial agents. Sensitivity of 100 Plasmodium falciparum isolates to chloroquine, quinine, amodiaquine, mefloquine, sulphadoxine/pyrimethamine, artemisinin, Momordica charantia ('Ejirin') Diospyros monbuttensis ('Egun eja') and Morinda lucida ('Oruwo') was determined using the in vitro microtest (Mark III) technique to determine the IC50 of the drugs. All the isolates tested were sensitive to quinine, mefloquine and artesunate. Fifty-one percent of the isolates were resistant to chloroquine, 13% to amodiaquine and 5% to sulphadoxine/pyrimethamine. Highest resistance to chloroquine (68.9%) was recorded among isolates from Yewa zone while highest resistance to amodiaquine (30%) was observed in Ijebu zone. Highest resistance to sulphadoxine/pyrimethamine was recorded in Yewa and Egba zones, respectively. A positive correlation was observed between the responses to artemisinin and mefloquine (P<0.05), artemisinin and quinine (P<0.05) and quinine and mefloquine (P<0.05). A negative correlation was observed between the responses to chloroquine and mefloquine (P>0.05). Highest anti-plasmodial activity was obtained with the ethanolic extract of D. monbuttensis (IC50 = 3.2 nM) while the lowest was obtained from M. lucida (IC50 = 25 nM). Natural products isolated from plants used in traditional medicine, which have potent anti-plasmodial action in vitro, represent potential sources of new anti-malarial drugs.

In vivo Antimalarial and Antitrypanosomal Activity of Strychnogucine B, a Bisindole Alkaloid from Strychnos icaja.

PubMed

Beaufay, Claire; Ledoux, Allison; Jansen, Olivia; Bordignon, Annélise; Zhao, Senzhi; Teijaro, Christiana N; Andrade, Rodrigo B; Quetin-Leclercq, Joëlle; Frédérich, Michel

2018-06-21

Strychnogucine B is a bisindole alkaloid previously isolated from Strychnos icaja that possesses promising in vitro antiplasmodial properties. This compound was synthesized in four steps from (-)-strychnine. As no acute toxicity was observed at the highest tested cumulative dose of 60 mg/kg, its in vivo antimalarial activity was determined intraperitoneally at 30 mg/kg/d in a Plasmodium berghei murine model. In the Peters's 4-d suppressive test, this alkaloid suppressed the parasitaemia by almost 36% on day 5 and 60% on day 7 compared to vehicle-treated mice. In addition to this interesting antimalarial activity, it showed moderate in vitro antitrypanosomal activity but no in vivo activity in an acute Trypanosoma brucei model. It was also inactive in vitro on Leishmania mexicana promastigotes. This highlights its selective antimalarial efficacy and leads to further investigation to assess its potential as new antimalarial lead compound. Georg Thieme Verlag KG Stuttgart · New York.

Phytochemical, antimicrobial and antiplasmodial investigations of Terminalia brownii

USDA-ARS?s Scientific Manuscript database

The stem bark of Terminalia brownii was collected from Machakos county, Kenya, in November 2011, and identified at the University Herbarium, School of Biological Sciences, University of Nairobi, where a voucher specimen (JM2011/502) was deposited. The stem bark was air dried in shade and pulverized....

Metallocene Antimalarials: The Continuing Quest

PubMed Central

Blackie, Margaret A. L.; Chibale, Kelly

2008-01-01

Over the last decade, a significant body of research has been developed around the inclusion of a metallocene moiety into known antimalarial compounds. Ferroquine is the most successful of these compounds. Herein, we describe our contribution to metallocene antimalarials. Our approach has sought to introduce diversity sites in the side chain of ferroquine in order to develop a series of ferroquine derivatives. The replacement of the ferrocenyl moiety with ruthenocene has given rise to ruthenoquine and a modest series of analogues. The reaction of ferroquine and selected analogues with Au(PPh3)NO3, Au(C6F5)(tht), and [Rh(COD)Cl2] has resulted in a series of heterobimetallic derivatives. In all cases, compounds have been evaluated for in vitro antiplasmodial activity in both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Preliminary structure-activity relationships have been delineated. PMID:18274662

Assessment of antiproliferative and antiplasmodial activities of five selected Apocynaceae species

PubMed Central

2011-01-01

Background Studies have shown that the barks and roots of some Apocynaceae species have anticancer and antimalarial properties. In this study, leaf extracts of five selected species of Apocynaceae used in traditional medicine (Alstonia angustiloba, Calotropis gigantea, Dyera costulata, Kopsia fruticosa and Vallaris glabra) were assessed for antiproliferative (APF) and antiplasmodial (APM) activities, and analysed for total alkaloid content (TAC), total phenolic content (TPC) and radical-scavenging activity (RSA). As V. glabra leaf extracts showed wide spectrum APF and APM activities, they were further screened for saponins, tannins, cardenolides and terpenoids. Methods APF and APM activities were assessed using the sulphorhodamine B and lactate dehydrogenase assays, respectively. TAC, TPC and RSA were analysed using Dragendorff precipitation, Folin-Ciocalteu and DPPH assays, respectively. Screening for saponins, tannins, cardenolides and terpenoids were conducted using the frothing, ferric chloride, Kedde and vanillin-H2SO4 tests, respectively. Results Leaf extracts of A. angustiloba, C. gigantea and V. glabra displayed positive APF activity. Dichloromethane (DCM) extract of C. gigantea, and DCM and DCM:MeOH extracts of V. glabra showed strong APF activity against all six human cancer cell lines tested. DCM extract of A. angustiloba was effective against three cancer cell lines. Against MCF-7 and MDA-MB-231 cell lines, DCM extract of C. gigantea was stronger than standard drugs of xanthorrhizol, curcumin and tamoxifen. All five species were effective against K1 strain of Plasmodium falciparum and three species (C. gigantea, D. costulata and K. fruticosa) were effective against 3D7 strain. Against K1 strain, all four extracts of V. glabra displayed effective APM activity. Extracts of D. costulata were effective against 3D7 strain. Selectivity index values of extracts of A. angustiloba, C. gigantea and V. glabra suggested that they are potentially safe for use to treat malaria. Extracts of K. fruticosa had the highest TAC while D. costulata had the highest TPC and RSA. Phytochemical screening of extracts of V. glabra also showed the presence of terpenoids, tannins and saponins. Conclusions Leaf extracts of C. gigantea and V. glabra showed great promise as potential candidates for anticancer drugs as they inhibited the growth of all six cancer cell lines. Against K1 strain of P. falciparum, all four extracts of V. glabra displayed effective APM activity. The wide spectrum APF and APM activities of V. glabra are reported for the first time and this warrants further investigation into its bioactive compounds. PMID:21232161

Antimalarial activity of methanolic leaf extract of Piper betle L.

PubMed

Al-Adhroey, Abdulelah H; Nor, Zurainee M; Al-Mekhlafi, Hesham M; Amran, Adel A; Mahmud, Rohela

2010-12-28

The need for new compounds active against malaria parasites is made more urgent by the rapid spread of drug-resistance to available antimalarial drugs. The crude methanol extract of Piper betle leaves (50-400 mg/kg) was investigated for its antimalarial activity against Plasmodium berghei (NK65) during early and established infections. The phytochemical and antioxidant potentials of the crude extract were evaluated to elucidate the possibilities of its antimalarial effects. The safety of the extract was also investigated in ICR mice of both sexes by the acute oral toxicity limit test. The leaf extract demonstrated significant (P < 0.05) schizonticidal activity in all three antimalarial evaluation models. Phytochemical screening showed that the leaf extract contains some vital antiplasmodial chemical constituents. The extract also exhibited a potent ability to scavenge the free radicals. The results of acute toxicity showed that the methanol extract of Piper betle leaves is toxicologically safe by oral administration. The results suggest that the Malaysian folklorical medicinal application of the extract of Piper betle leaf has a pharmacological basis.

Antimalarial pyrido[1,2-a]benzimidazoles.

PubMed

Ndakala, Albert J; Gessner, Richard K; Gitari, Patricia W; October, Natasha; White, Karen L; Hudson, Alan; Fakorede, Foluke; Shackleford, David M; Kaiser, Marcel; Yeates, Clive; Charman, Susan A; Chibale, Kelly

2011-07-14

A novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity and cytotoxicity following hits identified from screening commercially available compound collections. The most active of these, TDR86919 (4c), showed improved in vitro activity vs the drug-resistant K1 strain of Plasmodium falciparum relative to chloroquine (IC(50) = 0.047 μM v 0.17 μM); potency was retained against a range of drug-sensitive and drug-resistant strains, with negligible cytotoxicity against the mammalian (L-6) cell line (selectivity index of >600). 4c and several close analogues (as HCl or mesylate salts) showed significant efficacy in P. berghei infected mice following both intraperitoneal (ip) and oral (po) administration, with >90% inhibition of parasitemia, accompanied by an increase in the mean survival time (MSD). The pyrido[1,2-a]benzimidazoles appeared to be relatively slow acting in vivo compared to chloroquine, and metabolic stability of the alkylamino side chain was identified as a key issue in influencing in vivo activity.

In vitro antiplasmodial activity of crude extracts from Togolese medicinal plants.

PubMed

Koudouvo, Koffi; Karou, Simplice D; Ilboudo, Denise P; Kokou, Kouami; Essien, Kodjo; Aklikokou, Kodjo; de Souza, Comlan; Simpore, Jacques; Gbéassor, Mensavi

2011-02-01

To investigate the antimalarial effect of a few plants in Togo folk medicine. After ethnobotanical survey, Opilia celtidifolia, Pavetta corymbosa (P. corymbosa) and Tamarindus indica (T. indica) were selected for screening. In vitro antimalarial tests were performed on crude extracts against fresh clinical isolates of Plasmodium falciparum using the semi microtest. Different IC(50) values of the extracts ranged from 2.042 to 100.000 μg/mL. According to the results, the methanol extract of aerial part of P. corymbosa followed by aqueous extract of fruit of T. indica were the most active (IC(50) of 2.042 and 4.786 μg/mL, respectively). Qualitative test revealed the presence of alkaloids in the leaves of P. corymbosa that may be responsible for the activity of the plant. Our study provides scientific evidence for usage of plant in the folk medicine, and further studies are needed for identification and purification of the active principles. Copyright © 2011 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Assessment of the in vitro antiprotozoal and cytotoxic potential of 20 selected medicinal plants from the island of Soqotra.

PubMed

Mothana, Ramzi A; Al-Musayeib, Nawal M; Matheeussen, An; Cos, Paul; Maes, Louis

2012-12-03

Malaria, leishmaniasis and human African trypanosomiasis continue to be major public health problems in need of new and more effective drugs. The aim of this study was to evaluate in vitro antiprotozoal activity of twenty endemic medicinal plants collected from the island of Soqotra in the Indian Ocean. The plant materials were extracted with methanol and tested for antiplasmodial activity against erythrocytic schizonts of Plasmodium falciparum, for antileishmanial activity against intracellular amastigotes of Leishmania infantum and for antitrypanosomal activity against intracellular amastigotes of Trypanosoma cruzi and free trypomastigotes of T. brucei. To assess selectivity, cytotoxicity was determined against MRC-5 fibroblasts. Selective activity was obtained for Punica protopunica against Plasmodium (IC₅₀ 2.2 µg/mL) while Eureiandra balfourii and Hypoestes pubescens displayed activity against the three kinetoplastid parasites (IC₅₀ < 10 µg/mL). Acridocarpus socotranus showed activity against T. brucei and T. cruzi (IC₅₀ 3.5 and 8.4 µg/mL). Ballochia atrovirgata, Dendrosicycos socotrana, Dracaena cinnabari and Euphorbia socotrana displayed non-specific inhibition of the parasites related to high cytotoxicity.

In vitro synergistic effect of fluoroquinolone analogues in combination with artemisinin against Plasmodium falciparum; their antiplasmodial action in rodent malaria model.

PubMed

Agarwal, Drishti; Sharma, Manish; Dixit, Sandeep K; Dutta, Roshan K; Singh, Ashok K; Gupta, Rinkoo D; Awasthi, Satish K

2015-02-05

Emergence of drug-resistant parasite strains has surfaced as a major obstacle in attempts to ameliorate malaria. Current treatment regimen of malaria relies on the concept of artemisinin-based combination therapy (ACT). Fluoroquinolone analogues, compounds 10, 12 and 18 were investigated for their anti-malarial interaction in combination with artemisinin in vitro, against Plasmodium falciparum 3D7 strain, employing fixed-ratio combination isobologram method. In addition, the efficacy of these compounds was evaluated intraperitoneally in BALB/c mice infected with chloroquine-resistant Plasmodium berghei ANKA strain in the Peters' four-day suppressive test. Promising results were obtained in the form of synergistic or additive interactions. Compounds 10 and 12 were found to have highly synergistic interactions with artemisinin. Antiplasmodial effect was further verified by the convincing ED50 values of these compounds, which ranged between 2.31 and 3.09 (mg/kg BW). In vivo studies substantiated the potential of the fluoroquinolone derivatives to be developed as synergistic partners for anti-malarial drug combinations.

Influence of host factors and parasite biomass on the severity of imported Plasmodium falciparum malaria

PubMed Central

Kendjo, Eric; Augé-Courtoi, Claire; Cojean, Sandrine; Clain, Jérôme; Houzé, Pascal; Thellier, Marc; Hubert, Veronique; Deloron, Philippe; Houzé, Sandrine

2017-01-01

Objectives Imported malaria in France is characterized by various clinical manifestations observed in a heterogeneous population of patients such as travelers/expatriates and African migrants. In this population, host factors and parasite biomass associated with severe imported malaria are poorly known. Methods From data collected by the Centre National de Référence du Paludisme, we identified epidemiological, demographic and biological features including parasite biomass and anti-plasmodial antibody levels (negative, positive and strongly positive serology) associated with different disease severity groups (very severe, moderately severe, and uncomplicated malaria) in 3 epidemiological groups (travelers/expatriates, first- and second-generation migrants). Results Age, ethnicity, absence of prior infection with P. falciparum, antibody levels, plasma PfHRP2 levels, total and circulating parasite biomass were related to severe malaria onset. Sequestered parasite biomass tended to be increased in very severe malaria, and was strongly correlated to the antibody level of the host. Conclusions Prior exposure to P. falciparum is associated with high anti-plasmodial antibody levels which influence clinical presentation of imported malaria and its correlated circulating and sequestered parasite burden. PMID:28410415

Evaluation of the antiplasmodial and leishmanicidal potential of Myrciaria dubia (Myrtaceae) extract.

PubMed

Correia, Vanessa Carolina de Sena; Lima, Nathália Oliveira; Oliveira, Flávio Augusto de Souza; Santos, Ana Paula de Azevedo Dos; Teles, Carolina Bioni Garcia; Oliveira, Waldesse Piragé de; Pimenta, And Raphael Sanzio

2016-01-01

Malaria and leishmaniasis are prevalent in tropical regions, which have environmental characteristics that are highly favorable to protozoa and vectors of these diseases; the transmission of these infections in sub-tropical regions, although recognized, represents only a small fraction of cases. Plants are constantly being used in the search for and acquisition of new drugs, and many compounds derived from them have been used to combat various diseases. In this study, we evaluated the action of the dichloromethanolic extract of Myrciaria dubia leaves against the protozoa Plasmodium falciparum, Leishmania amazonensis, Leishmania braziliensis, and Leishmania chagasi through bioassays. The extract from M. dubia was tested for its anti-P. falciparum activity in an anti-histidine-rich protein II immunosorbent assay. The antileishmanial assays were performed using the resazurin method, while cytotoxicity against human hepatoma (HepG2) strain was determined using the colorimetric MTT [3-(4, 5-dimethyl-2- thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide] method. The M. dubia extract presented a half-maximal inhibitory concentration equal to 2.35 (1.05)μg/mL for P. falciparum, 190.73 (6.41) μg/mL for L. amazonensis, and greater than equal to 200µg/mL for L. chagasi and L. braziliensis strains. The cytotoxic concentration for 50% of the cells was above 500μg/mL for HepG2, indicating no toxicity and greater selectivity against parasites. The results obtained indicate the presence of antiplasmodial and leishmanicidal bioactive compounds in the dichloromethanolic extracts of M. dubia leaves, and point towards future studies to elucidate the mechanism of action for each physiological effect.

In vitro studies on the sensitivity pattern of Plasmodium falciparum to anti-malarial drugs and local herbal extracts

PubMed Central

2014-01-01

Background The resistance of human malaria parasites to anti-malarial compounds has become considerable concern, particularly in view of the shortage of novel classes of anti-malarial drugs. One way to prevent resistance is by using new compounds that are not based on existing synthetic antimicrobial agents. Results Sensitivity of 100 Plasmodium falciparum isolates to chloroquine, quinine, amodiaquine, mefloquine, sulphadoxine/pyrimethamine, artemisinin, Momordica charantia (‘Ejirin’) Diospyros monbuttensis (‘Egun eja’) and Morinda lucida (‘Oruwo’) was determined using the in vitro microtest (Mark III) technique to determine the IC50 of the drugs. All the isolates tested were sensitive to quinine, mefloquine and artesunate. Fifty-one percent of the isolates were resistant to chloroquine, 13% to amodiaquine and 5% to sulphadoxine/pyrimethamine. Highest resistance to chloroquine (68.9%) was recorded among isolates from Yewa zone while highest resistance to amodiaquine (30%) was observed in Ijebu zone. Highest resistance to sulphadoxine/pyrimethamine was recorded in Yewa and Egba zones, respectively. A positive correlation was observed between the responses to artemisinin and mefloquine (P<0.05), artemisinin and quinine (P<0.05) and quinine and mefloquine (P<0.05). A negative correlation was observed between the responses to chloroquine and mefloquine (P>0.05). Highest anti-plasmodial activity was obtained with the ethanolic extract of D. monbuttensis (IC50 = 3.2nM) while the lowest was obtained from M. lucida (IC50 =25nM). Conclusions Natural products isolated from plants used in traditional medicine, which have potent anti-plasmodial action in vitro, represent potential sources of new anti-malarial drugs. PMID:24555525

Cross-sectional study defines difference in malaria morbidity in two Yanomami communities on Amazonian boundary between Brazil and Venezuela.

PubMed

Marcano, Teodardo José; Morgado, Anastácio; Tosta, Carlos Eduardo; Coura, José Rodrigues

2004-06-01

It is well established that immunity to malaria is short-lived and is maintained by the continuous contact with the parasite. We now show that the stable transmission of malaria in Yanomami Amerindian communities maintains a degree of immunity in the exposed population capable to reduce prevalence and morbidity of malaria. We examined 508 Yanomami Amerindians living along Orinoco (407) and Mucajaí (101) rivers, on the Venezuelan and Brazilian Amazon region, respectively. At Orinoco villages, malaria was hyperendemic and presented stable transmission, while at Mucajaí villages it was mesoendemic and showed unstable transmission. The frequency of Plasmodium vivax and P. falciparum was roughly comparable in Venezuelan and Brazilian communities. Malaria presented different profiles at Orinoco and Mucajaí villages. In the former communities, malaria showed a lower prevalence (16% x 40.6%), particularly among those over 10 years old (5.2% x 34.8%), a higher frequency of asymptomatic cases (38.5% x 4.9%), and a lower frequency of cases of severe malaria (9.2% x 36.5%). Orinoco villagers also showed a higher reactivity of the immune system, measured by the frequency of splenomegaly (72.4% x 29.7%) and by the splenic index (71.4% over level 1 x 28.6), and higher prevalence (91.1% x 72.1%) and mean titer (1243 x 62) of antiplasmodial IgG antibodies, as well as a higher prevalence (77.4% x 24.7%) and mean titer (120 x 35) of antiplasmodial IgM antibodies. Our findings show that in isolated Yanomami communities the stability of malaria transmission, and the consequent continuous activation of the immune system of the exposed population, leads to the reduction of malaria prevalence and morbidity.

Antiplasmodial, beta-haematin inhibition, antitrypanosomal and cytotoxic activity in vitro of novel 4-aminoquinoline 2-imidazolines.

PubMed

Musonda, Chitalu C; Yardley, Vanessa; de Souza, Renata C Carvalho; Ncokazi, Kanyile; Egan, Timothy J; Chibale, Kelly

2008-12-07

A novel series of 4-aminoquinoline-containing 2-imidazolines were synthesized via a one-pot 3-component condensation reaction of amine, aldehyde and isocyanoacetate. The products were obtained in high yield as well as purity and were evaluated directly against two strains of Plasmodium falciparum and Trypanosoma brucei. Compound was the most active across all parasites with ED(50) = 3.3 nM against a chloroquine (CQ)-sensitive 3D7 strain, ED(50) = 33 nM against a CQ-resistant K1 strain and ED(50) = 70 nM against T. brucei. Several compounds were able to inhibit formation of beta-haematin in vitro, suggesting haemozoin formation in the malaria parasite as a possible target. On the other hand, evaluation against a human KB cell line revealed that the compounds were generally non-cytotoxic to the host cells.

Isolation, pharmacological activity and structure determination of physalin B and 5β,6β-epoxyphysalin B isolated from Congolese Physalis angulata L.

PubMed

Mangwala Kimpende, Peter; Lusakibanza, Mariano; Mesia, Kahunu; Tona, Lutete; Tits, Monique; Angenot, Luc; Frédérich, Michel; Van Meervelt, Luc

2013-12-15

Physalis angulata L., an annual herb from the Solanaceae family, is widely used in popular medicine in tropical countries to treat a variety of diseases. Two products, (X) and (Y), were isolated from a crude CH2Cl2 extract of dried Congolese Physalis angulata L. plants and crystallized from acetone for structure elucidation. Compound (X) corresponds to a physalin B dimer acetone solvate hydrate (2C28H30O9·C3H6O·0.22H2O), while compound (Y) crystallizes as a mixed crystal containing two physalin B molecules which overlap with 5β,6β-epoxyphysalin B, also known as physalin F, and one acetone molecule in the asymmetric unit (1.332C28H30O9·0.668C28H30O10·C3H6O). Antiplasmodial activity, cytotoxic activity and selectivity indices were determined for crude extracts and the two isolated products (X) and (Y).

1,2-disubstituted ferrocenyl carbohydrate chloroquine conjugates as potential antimalarial agents.

PubMed

Herrmann, Christoph; Salas, Paloma F; Patrick, Brian O; de Kock, Carmen; Smith, Peter J; Adam, Michael J; Orvig, Chris

2012-06-07

This work presents a new family of organometallic antimalarial compounds consisting of ferrocene bearing a chloroquine-derived moiety as well as a 1,2;3,5-diisopropylidene glucofuranose moiety at a cyclopentadienyl scaffold in a 1,2-substitution pattern. The synthetic route proceeds via a stereoselective functionalization of ferrocene carboxaldehyde to the 1,2-disubstituted conjugates. After complete characterization of these new, trifunctional conjugates, they were examined for their cytotoxicity in two cancerous cell lines (MDA-MB-435S and Caco2) and one non-cancerous cell line (MCF-10A), showing that increased cytotoxicity can be observed for the chloroquine ferrocenyl conjugates compared to their carbohydrate-substituted precursors. The antiplasmodial activity of the conjugates in a chloroquine-sensitive strain of Plasmodium falciparum (D10) and a chloroquine-resistant strain (Dd2) was determined. Monosubstituted conjugates 13, 14 and 15 exhibit decreasing activity with increasing alkyl chain length between the ferrocene and quinoline moiety, bifunctional conjugates 16, 17, 18 show constant activity, performing better than chloroquine in the Dd2 strain.

Antiplasmodial activity of compounds from Sloanea rhodantha (Baker) Capuron var. rhodantha from the Madagascar rain forest.

PubMed

Cao, Shugeng; Ranarivelo, Lalasoa; Ratsimbason, Michel; Randrianasolo, Sennen; Ratovoson, Fidy; Andrianjafy, Mamisoa; Kingston, David G I

2006-12-01

Bioassay-directed separation of the butanol-soluble portion of an extract of Sloanea rhodantha (Baker) Capuron var. Rhodantha (Elaeocarpaceae) active against the drug-sensitive HB3 strain of Plasmodium falciparum led to the isolation of seven phenolic compounds, gallic acid (1), 3,5-di-O-galloylquinic acid (2), 1,6-di-O-galloyl glucopyranoside (3), 3,4,5-tri-O-galloylquinic acid (4), 1-O-eudesmoylquinic acid (5), 1,2,3,6-tetra-O-galloyl glucopyranoside (6), and 3,4,5-trimethoxyphenyl-(6'-O-galloyl)-O-b-D-glucopyranoside (7). The structure of the new compound 5 was established on the basis of interpretation of its 1D and 2D NMR spectroscopic data. Compounds 2, 3, 4, 6, and 7 showed weak inhibitory activity against the drug-sensitive HB3 and the drug-resistant FCM29 strains of P. falciparum, with IC (50) values ranging from 8.0 - 43.0 and 16.1 - 93.0 microg/mL, respectively.

Assessing sub-Saharan Erythrina for efficacy: traditional uses, biological activities and phytochemistry.

PubMed

Kone, Witabouna Mamidou; Solange, Kakou-Ngazoa E; Dosso, Mireille

2011-05-15

The genus Erythrina comprises more than 100 species, widely distributed in tropical and subtropical areas. In Africa, 31 wild species and 14 cultivated species have been described. In sub-Saharan Africa, Erythrina species are used to treat frequent parasitic and microbial diseases, inflammation, cancer, wounds. The rationale of these traditional uses in African traditional medicine was established by screening several species for biological activities. Promising activities were found against bacteria, parasites (Plasmodium), human and phytopathogenic fungi, some of which were multidrug resistant (MDR) micro organisms. Some species also exhibited antioxidant, anti-inflammatory activities and enzymes inhibitory properties. Most of the species chemically investigated were reported to contain flavanones, prenylated isoflavones, isoflavanones and pterocarpans. Some phytochemicals (vogelin B, vogelin C, isowightcone, abyssinin II, derrone) were the active principles as antibacterials, antifungals, antiplasmodials and inhibitors of enzyme borne diseases (PTP1B, HIV protease, DGAT). This review highlights the important role of Erythrina species as sources of lead compounds or new class of phytotherapeutic agents for fighting against major public health (MDR infections, cancer, diabetes, obesity) in sub-Saharan Africa.

Pentacyclic ingamine-type alkaloids, a new antiplasmodial pharmacophore from the marine sponge petrosid Ng5 Sp5

USDA-ARS?s Scientific Manuscript database

Two new pentacyclic ingamine- type alkaloids, namely 22(S)-hydroxyingamine A (2) and dihydroingenamine D (3), together with the known ingamine A (1) have been isolated from marine sponge Petrosid Ng5 Sp5 (Family: Petrosiidae) obtained from the open repository of National Cancer Institute, USA. The s...

Transmission blocking activity of a standardized neem (Azadirachta indica) seed extract on the rodent malaria parasite Plasmodium berghei in its vector Anopheles stephensi

PubMed Central

2010-01-01

Background The wide use of gametocytocidal artemisinin-based combination therapy (ACT) lead to a reduction of Plasmodium falciparum transmission in several African endemic settings. An increased impact on malaria burden may be achieved through the development of improved transmission-blocking formulations, including molecules complementing the gametocytocidal effects of artemisinin derivatives and/or acting on Plasmodium stages developing in the vector. Azadirachtin, a limonoid (tetranortriterpenoid) abundant in neem (Azadirachta indica, Meliaceae) seeds, is a promising candidate, inhibiting Plasmodium exflagellation in vitro at low concentrations. This work aimed at assessing the transmission-blocking potential of NeemAzal®, an azadirachtin-enriched extract of neem seeds, using the rodent malaria in vivo model Plasmodium berghei/Anopheles stephensi. Methods Anopheles stephensi females were offered a blood-meal on P. berghei infected, gametocytaemic BALB/c mice, treated intraperitoneally with NeemAzal, one hour before feeding. The transmission-blocking activity of the product was evaluated by assessing oocyst prevalence, oocyst density and capacity to infect healthy mice. To characterize the anti-plasmodial effects of NeemAzal® on early midgut stages, i.e. zygotes and ookinetes, Giemsa-stained mosquito midgut smears were examined. Results NeemAzal® completely blocked P. berghei development in the vector, at an azadirachtin dose of 50 mg/kg mouse body weight. The totally 138 examined, treated mosquitoes (three experimental replications) did not reveal any oocyst and none of the healthy mice exposed to their bites developed parasitaemia. The examination of midgut content smears revealed a reduced number of zygotes and post-zygotic forms and the absence of mature ookinetes in treated mosquitoes. Post-zygotic forms showed several morphological alterations, compatible with the hypothesis of an azadirachtin interference with the functionality of the microtubule organizing centres and with the assembly of cytoskeletal microtubules, which are both fundamental processes in Plasmodium gametogenesis and ookinete formation. Conclusions This work demonstrated in vivo transmission blocking activity of an azadirachtin-enriched neem seed extract at an azadirachtin dose compatible with 'druggability' requisites. These results and evidence of anti-plasmodial activity of neem products accumulated over the last years encourage to convey neem compounds into the drug discovery & development pipeline and to evaluate their potential for the design of novel or improved transmission-blocking remedies. PMID:20196858

Preparative isolation, fast centrifugal partition chromatography purification and biological activity of cajaflavanone from Derris ferruginea stems.

PubMed

Morel, Sylvie; Landreau, Anne; Nguyen, Van Hung; Derbré, Séverine; Grellier, Philippe; Pape, Patrice Le; Pagniez, Fabrice; Litaudon, Marc; Richomme, Pascal

2012-01-01

The Derris genus is known to contain flavonoid derivatives, including prenylated flavanones and isoflavonoids such as rotenoids, which are generally associated with significant biological activity. To develop an efficient preparative isolation procedure for bioactive cajaflavanone. Fast centrifugal partition chromatography (FCPC) was optimised to purify cajaflavanone from Derris ferruginea stems in a single step as compared to fractionation from the cyclohexane extract by successive conventional solid-liquid chromatography procedures. The purification yield, purity, time and solvent consumption per procedure are described. The anti-fungal, anti-bacterial, anti-leishmanial, anti-plasmodial, anti-oxidant activities and the inhibition of advanced glycation end-products (AGEs) by cajaflavanone accumulation are described. FCPC enabled cajaflavanone purification in a single separation step, yielding sufficient quantities to perform in vitro biological screening. Interestingly, cajaflavanone had an inhibitory effect on the formation of AGEs, without displaying any in vitro anti-oxidant activity. A simple and efficient procedure, in comparison with other preparative methods, for bioactive cajaflavone purification has been developed using FCPC. Copyright © 2011 John Wiley & Sons, Ltd.

Monoterpenes with antibacterial activities from a Cameroonian medicinal plant Canthium Multiflorum (Rubiaceae).

PubMed

Kouam, Simeon Fogue; Ngouonpe, Alain Wembe; Bullach, Anke; Lamshöft, Marc; Kuigoua, Guy Merlin; Spiteller, Michael

2013-12-01

Investigation of the crude extract obtained from the aerial parts of Canthium multiflorum led to the isolation of a new iridoid (1) together with twelve known compounds. The structures of these compounds were elucidated by interpretation of 1D and 2D NMR spectroscopic data, accurate mass measurements and comparison with analytical data of previously known analogues. Most of the isolated compounds have been reported for the first time from C. multiflorium. The antimicrobial activities of the isolated compounds were evaluated on five different bacterial strains using agar diffusion technique. The Gram-positive bacterium Staphylococcus aureus subsp. aureus (DSM 799), and the Gram-negative bacteria Actinobacter calco-aceticus (DSM 30006), Serratia plymuthica (DSM 4540), Pseudomonas stutzeri (DSM 4166) and Escherichia coli (DSM 1116) were employed for this purpose. The new iridoid, named 6-oxo-genipin (1), demonstrated significant inhibitory activity against all microbial strains tested, especially the pathogen Staphylococcus aureus. In addition, the compounds 3, 4 and 9 exhibited antiplasmodial activity against Plasmodium falciparum strain K1 and weak cytotoxicity against L6 cell lines. © 2013 Elsevier B.V. All rights reserved.

Chlorpheniramine Analogues Reverse Chloroquine Resistance in Plasmodium falciparum by Inhibiting PfCRT.

PubMed

Deane, Karen J; Summers, Robert L; Lehane, Adele M; Martin, Rowena E; Barrow, Russell A

2014-05-08

The emergence and spread of malaria parasites that are resistant to chloroquine (CQ) has been a disaster for world health. The antihistamine chlorpheniramine (CP) partially resensitizes CQ-resistant (CQR) parasites to CQ but possesses little intrinsic antiplasmodial activity. Mutations in the parasite's CQ resistance transporter (PfCRT) confer resistance to CQ by enabling the protein to transport the drug away from its site of action, and it is thought that resistance-reversers such as CP exert their effect by blocking this CQ transport activity. Here, a series of new structural analogues and homologues of CP have been synthesized. We show that these compounds (along with other in vitro CQ resistance-reversers) inhibit the transport of CQ via a resistance-conferring form of PfCRT expressed in Xenopus laevis oocytes. Furthermore, the level of PfCRT-inhibition was found to correlate well with both the restoration of CQ accumulation and the level of CQ resensitization in CQR parasites.

Functional screening of selective mitochondrial inhibitors of Plasmodium.

PubMed

Gomez-Lorenzo, Maria G; Rodríguez-Alejandre, Ane; Moliner-Cubel, Sonia; Martínez-Hoyos, María; Bahamontes-Rosa, Noemí; Gonzalez Del Rio, Rubén; Ródenas, Carolina; Fuente, Jesús de la; Lavandera, Jose Luis; García-Bustos, Jose F; Mendoza-Losana, Alfonso

2018-05-09

Phenotypic screening has produced most of the new chemical entities currently in clinical development for malaria, plus many lead compounds active against Plasmodium falciparum asexual stages. However, lack of knowledge about the mode of action of these compounds delays and may even hamper their future development. Identifying the mode of action of the inhibitors greatly helps to prioritise compounds for further development as novel antimalarials. Here we describe a whole-cell method to detect inhibitors of the mitochondrial electron transport chain, using oxygen consumption as high throughput readout in 384-well plate format. The usefulness of the method has been confirmed with the Tres Cantos Antimalarial Compound Set (TCAMS). The assay identified 124 respiratory inhibitors in TCAMS, seven of which were novel anti-plasmodial chemical structures never before described as mitochondrial inhibitors. Copyright © 2018. Published by Elsevier Ltd.

HSQC-TOCSY Fingerprinting for Prioritization of Polyketide- and Peptide-Producing Microbial Isolates.

PubMed

Buedenbender, Larissa; Habener, Leesa J; Grkovic, Tanja; Kurtböke, D İpek; Duffy, Sandra; Avery, Vicky M; Carroll, Anthony R

2018-04-27

Microbial products are a promising source for drug leads as a result of their unique structural diversity. However, reisolation of already known natural products significantly hampers the discovery process, and it is therefore important to incorporate effective microbial isolate selection and dereplication protocols early in microbial natural product studies. We have developed a systematic approach for prioritization of microbial isolates for natural product discovery based on heteronuclear single-quantum correlation-total correlation spectroscopy (HSQC-TOCSY) nuclear magnetic resonance profiles in combination with antiplasmodial activity of extracts. The HSQC-TOCSY experiments allowed for unfractionated microbial extracts containing polyketide and peptidic natural products to be rapidly identified. Here, we highlight how this approach was used to prioritize extracts derived from a library of 119 ascidian-associated actinomycetes that possess a higher potential to produce bioactive polyketides and peptides.

A potent, covalent inhibitor of orotidine 5'-monophosphate decarboxylase with antimalarial activity.

PubMed

Bello, Angelica M; Poduch, Ewa; Fujihashi, Masahiro; Amani, Merhnaz; Li, Yan; Crandall, Ian; Hui, Raymond; Lee, Ping I; Kain, Kevin C; Pai, Emil F; Kotra, Lakshmi P

2007-03-08

Orotidine 5'-monophosphate decarboxylase (ODCase) has evolved to catalyze the decarboxylation of orotidine 5'-monophosphate without any covalent intermediates. Active site residues in ODCase are involved in an extensive hydrogen-bonding network. We discovered that 6-iodouridine 5'-monophosphate (6-iodo-UMP) irreversibly inhibits the catalytic activities of ODCases from Methanobacterium thermoautotrophicum and Plasmodium falciparum. Mass spectral analysis of the enzyme-inhibitor complex confirms covalent attachment of the inhibitor to ODCase accompanied by the loss of two protons and the iodo moiety. The X-ray crystal structure (1.6 A resolution) of the complex of the inhibitor and ODCase clearly shows the covalent bond formation with the active site Lys-72 [corrected] residue. 6-Iodo-UMP inhibits ODCase in a time- and concentration-dependent fashion. 6-Iodouridine, the nucleoside form of 6-iodo-UMP, exhibited potent antiplasmodial activity, with IC50s of 4.4 +/- 1.3 microM and 6.2 +/- 0.7 microM against P. falciparum ItG and 3D7 isolates, respectively. 6-Iodouridine 5'-monophosphate is a novel covalent inhibitor of ODCase, and its nucleoside analogue paves the way to a new class of inhibitors against malaria.

Elephantorrhiza elephantina: Traditional Uses, Phytochemistry, and Pharmacology of an Important Medicinal Plant Species in Southern Africa

PubMed Central

2017-01-01

Elephantorrhiza elephantina is used in southern Africa as traditional remedy for a wide range of human diseases and ailments including dermatological diseases, gastrointestinal system disorders, sexual dysfunction, sexually transmitted infections, and wounds. The rhizome decoction of E. elephantina is widely used by small-scale farmers in Botswana and South Africa as ethnoveterinary medicine for cattle, goats, horses, pigs, poultry, and sheep. Several classes of phytochemical compounds including anthocyanidins, anthraquinones, esters, fatty acids, phenolic compounds, flavonoids, glycosides, polysterols, saponins, sugars, tannins, and triterpenoids have been isolated from E. elephantina. Scientific studies on E. elephantina indicate that it has a wide range of biological activities including anthelmintic, antibacterial, antifungal, anti-inflammatory and antinociceptive, antiplasmodial, antioxidant, antibabesial, and antirickettsial activities. Elephantorrhiza elephantina is a valuable source of traditional medicine in southern Africa that it is worth additional research attention because of its wide ethnomedicinal applications and promising biological activities. However, the current health-related information on E. elephantina is not sufficiently explored as diverse studies on its chemical and pharmacological activities are required to understand its mechanism of action and to characterize the metabolites responsible for these activities. PMID:28588639

In vivo antimalarial activity of a labdane diterpenoid from the leaves of Otostegia integrifolia Benth.

PubMed

Endale, Abyot; Bisrat, Daniel; Animut, Abebe; Bucar, Franz; Asres, Kaleab

2013-12-01

In Ethiopian traditional medicine, the leaves of Otostegia integrifolia Benth. are used for the treatment of several diseases including malaria. In an ongoing search for effective, safe and cheap antimalarial agents from plants, the 80% methanol leaf extract O. integrifolia was tested for its in vivo antimalarial activity, in a 4-day suppressive assay against Plasmodium berghei. Activity-guided fractionation of this extract which showed potent antiplasmodial activity resulted in the isolation of a labdane diterpenoid identified as otostegindiol. Otostegindiol displayed a significant (P < 0.001) antimalarial activity at doses of 25, 50 and 100 mg/kg with chemosuppression values of 50.13, 65.58 and 73.16%, respectively. Acute toxicity studies revealed that the crude extract possesses no toxicity in mice up to a maximum dose of 5000 mg/kg suggesting the relative safety of the plant when administered orally. The results of the present study indicate that otostegindiol is among the antimalarial principles in this medicinal plant, and further support claims for the traditional medicinal use of the plant for the treatment of malaria. Copyright © 2013 John Wiley & Sons, Ltd.

Antiplasmodial Activity of [(Aryl)arylsulfanylmethyl]Pyridine▿ †‡

PubMed Central

Kumar, Sanjay; Das, Sajal Kumar; Dey, Sumanta; Maity, Pallab; Guha, Mithu; Choubey, Vinay; Panda, Gautam; Bandyopadhyay, Uday

2008-01-01

A series of [(aryl)arylsufanylmethyl]pyridines (AASMP) have been synthesized. These compounds inhibited hemozoin formation, formed complexes (KD = 12 to 20 μM) with free heme (ferriprotoporphyrin IX) at a pH close to the pH of the parasite food vacuole, and exhibited antimalarial activity in vitro. The inhibition of hemozoin formation may develop oxidative stress in Plasmodium falciparum due to the accumulation of free heme. Interestingly, AASMP developed oxidative stress in the parasite, as evident from the decreased level of glutathione and increased formation of lipid peroxide, H2O2, and hydroxyl radical (·OH) in P. falciparum. AASMP also caused mitochondrial dysfunction by decreasing mitochondrial potential (ΔΨm) in malaria parasite, as measured by both flow cytometry and fluorescence microscopy. Furthermore, the generation of ·OH may be mainly responsible for the antimalarial effect of AASMP since ·OH scavengers such as mannitol, as well as spin trap α-phenyl-n-tertbutylnitrone, significantly protected P. falciparum from AASMP-mediated growth inhibition. Cytotoxicity testing of the active compounds showed selective activity against malaria parasite with selectivity indices greater than 100. AASMP also exhibited profound antimalarial activity in vivo against chloroquine resistant P. yoelii. Thus, AASMP represents a novel class of antimalarial. PMID:18025110

Euclea undulata Thunb.: Review of its botany, ethnomedicinal uses, phytochemistry and biological activities.

PubMed

Maroyi, Alfred

2017-11-01

Euclea undulata (E. undulata) is traditionally used for the treatment of body pains, chest complaints, cough, diabetes, diarrhoea, headaches, heart diseases and toothaches in southern Africa. This study was aimed at reviewing the botany, ethnopharmacology and biological activities of E. undulata in southern Africa. Results presented in this study are based on review of literature using search engines such as Science Direct, Springerlink, Scopus, PubMed, Web of Science, BioMed Central and Google Scholar. Herbal medicine is prepared from the decoctions of the roots, bark and leaves, and extracts of these plant parts have demonstrated anticholinesterase, anti-inflammatory, antimicrobial, antimycobacterial, antiplasmodial, antioxidant and hypoglycaemic activities. Multiple classes of phytochemical compounds such alkaloids, diterpenes, fatty acids, flavonoids, glycosides, naphthoquinones, phenolics, phytosterols, reducing sugars, saponins and tannins have been isolated from the species. E. undulata has a lot of potential as herbal medicine in tropical Africa, and advanced research is required aimed at correlating its medicinal uses with the phytochemistry and pharmacological properties. Copyright © 2017 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.

New hydrazine and hydrazide quinoxaline 1,4-di-N-oxide derivatives: In silico ADMET, antiplasmodial and antileishmanial activity.

PubMed

Quiliano, Miguel; Pabón, Adriana; Ramirez-Calderon, Gustavo; Barea, Carlos; Deharo, Eric; Galiano, Silvia; Aldana, Ignacio

2017-04-15

We report the design (in silico ADMET criteria), synthesis, cytotoxicity studies (HepG-2 cells), and biological evaluation of 15 hydrazine/hydrazide quinoxaline 1,4-di-N-oxide derivatives against the 3D7 chloroquine sensitive strain and FCR-3 multidrug resistant strain of Plasmodium falciparum and Leishmania infantum (axenic amastigotes). Fourteen of derivatives are novel quinoxaline 1,4-di-N-oxide derivatives. Compounds 18 (3D7 IC 50 =1.40μM, FCR-3 IC 50 =2.56μM) and 19 (3D7 IC 50 =0.24μM, FCR-3 IC 50 =2.8μM) were identified as the most active against P. falciparum, and they were the least cytotoxic (CC 50 -values>241μM) and most selective (SI>86). None of the compounds tested against L. infantum were considered to be active. Additionally, the functional role of the hydrazine and hydrazide structures were studied in the quinoxaline 1,4-di-N-oxide system. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Malaria serology test: what contribution does it make in an endemic country such as Ivory Coast?

PubMed

Goran-Kouacou, Amah Patricia Victorine; Dou, Gonat Serge; Zika, Kalou Dibert; Adou, Adjoumanvoulé Honoré; Yéboah, Oppong Richard; Aka, Rita Ahou; Hien, Sansan; Siransy, Kouabla Liliane; N'Guessan, Koffi; Djibangar, Tariam Agnès; Dassé, Séry Romuald; Adoubryn, Koffi Daho

2017-01-01

Malaria serology test seems to have attracted very little interest in endemic countries such as Ivory Coast. However, this examination has been regularly performed in the parasitology laboratory at the Training and Research Unit of Medical Sciences in Abidjan. Our study aimed to highlight the contribution of malaria serology test in our endemic country context. We conducted a retrospective study of malaria serology test using Falciparum-Spot IF (bioMerieux) kit for the detection of IgG antiplasmodial antibodies. It included all malaria serology tests performed from January 2007 to February 2011 and whose results were available in the registry. In total, 136 patients were selected. The average age of patients was 36,3 years, ranging from 1 to 81 years, and sex ratio was 0,97. Indications for malaria serology test were varied and dominated by splenomegaly (49.3%), cytopenias (14.7%), indeterminate fever (13.2%). Almost all of the patients (98.5%) had antiplasmodial antibodies with high medium titer of 1057,35IU/ml. There was no link between age and Ab titer, which was higher in cytopenias, prolonged fevers and the splenomegaly. Malaria serology test seems to have attracted very little interest in routine clinical practice provided in our endemic area because, whatever the reason of the prescription, titers were high.

4-Aminoquinoline derivatives: Synthesis, in vitro and in vivo antiplasmodial activity against chloroquine-resistant parasites.

PubMed

Singh, Shailja; Agarwal, Drishti; Sharma, Kumkum; Sharma, Manish; Nielsen, Morten A; Alifrangis, Michael; Singh, Ashok K; Gupta, Rinkoo D; Awasthi, Satish K

2016-10-21

Synthetic quinoline derivatives continue to be considered as candidates for new drug discovery if they act against CQ-resistant strains of malaria even after the widespread emergence of resistance to CQ. In this study, we explored the activities of two series of new 4-aminoquinoline derivatives and found them to be effective against Plasmodium falciparum under in vitro conditions. Further, we selected four most active derivatives 1m, 1o, 2c and 2j and evaluated their antimalarial potential against Plasmodium berghei in vivo. These 4-aminoquinolines cured BALB/c mice infected with P. berghei. The ED50 values were calculated to be 2.062, 2.231, 1.431, 1.623 and 1.18 mg/kg of body weight for each of the compounds 1m, 1o, 2c, 2j and amodiaquine, respectively. Total doses of 500 mg/kg of body weight were well received. The study suggests that these new 4-aminoquinolines should be used for structure activity relationship to find lead molecules for treating multidrug-resistant Plasmodium falciparum and Plasmodium vivax. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

4-Nitro styrylquinoline is an antimalarial inhibiting multiple stages of Plasmodium falciparum asexual life cycle.

PubMed

Roberts, Bracken F; Zheng, Yongsheng; Cleaveleand, Jacob; Lee, Sukjun; Lee, Eunyoung; Ayong, Lawrence; Yuan, Yu; Chakrabarti, Debopam

2017-04-01

Drugs against malaria are losing their effectiveness because of emerging drug resistance. This underscores the need for novel therapeutic options for malaria with mechanism of actions distinct from current antimalarials. To identify novel pharmacophores against malaria we have screened compounds containing structural features of natural products that are pharmacologically relevant. This screening has identified a 4-nitro styrylquinoline (SQ) compound with submicromolar antiplasmodial activity and excellent selectivity. SQ exhibits a cellular action distinct from current antimalarials, acting early on malaria parasite's intraerythrocytic life cycle including merozoite invasion. The compound is a fast-acting parasitocidal agent and also exhibits curative property in the rodent malaria model when administered orally. In this report, we describe the synthesis, preliminary structure-function analysis, and the parasite developmental stage specific action of the SQ scaffold. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues.

PubMed

Vallone, Alessandra; D'Alessandro, Sarah; Brogi, Simone; Brindisi, Margherita; Chemi, Giulia; Alfano, Gloria; Lamponi, Stefania; Lee, Soon Goo; Jez, Joseph M; Koolen, Karin J M; Dechering, Koen J; Saponara, Simona; Fusi, Fabio; Gorelli, Beatrice; Taramelli, Donatella; Parapini, Silvia; Caldelari, Reto; Campiani, Giuseppe; Gemma, Sandra; Butini, Stefania

2018-04-25

Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection of 25 for further biological investigation. The potential transmission blocking activity of 25 versus P. falciparum was confirmed through the standard membrane-feeding assay. Both 1 and 25 significantly prolonged atrioventricular conduction time in Langendorff-isolated rat hearts, and showed inhibitory activity of Ba 2+ current through Ca v 1.2 channels. An in silico target-fishing study suggested the enzyme phosphoethanolamine methyltransferase (PfPMT) as a potential target. However, compound activity against PfPMT did not track with the antiplasmodial activity, suggesting the latter activity relies on a different molecular target. Nevertheless, 25 showed interesting activity against PfPMT, which could be an important starting point for the identification of more potent inhibitors active against both sexual and asexual stages of the parasite. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Discovery of New Compounds Active against Plasmodium falciparum by High Throughput Screening of Microbial Natural Products.

PubMed

Pérez-Moreno, Guiomar; Cantizani, Juan; Sánchez-Carrasco, Paula; Ruiz-Pérez, Luis Miguel; Martín, Jesús; El Aouad, Noureddine; Pérez-Victoria, Ignacio; Tormo, José Rubén; González-Menendez, Víctor; González, Ignacio; de Pedro, Nuria; Reyes, Fernando; Genilloud, Olga; Vicente, Francisca; González-Pacanowska, Dolores

2016-01-01

Due to the low structural diversity within the set of antimalarial drugs currently available in the clinic and the increasing number of cases of resistance, there is an urgent need to find new compounds with novel modes of action to treat the disease. Microbial natural products are characterized by their large diversity provided in terms of the chemical complexity of the compounds and the novelty of structures. Microbial natural products extracts have been underexplored in the search for new antiparasitic drugs and even more so in the discovery of new antimalarials. Our objective was to find new druggable natural products with antimalarial properties from the MEDINA natural products collection, one of the largest natural product libraries harboring more than 130,000 microbial extracts. In this work, we describe the optimization process and the results of a phenotypic high throughput screen (HTS) based on measurements of Plasmodium lactate dehydrogenase. A subset of more than 20,000 extracts from the MEDINA microbial products collection has been explored, leading to the discovery of 3 new compounds with antimalarial activity. In addition, we report on the novel antiplasmodial activity of 4 previously described natural products.

Antimalarial Activity of the Chemical Constituents of the Leaf Latex of Aloe pulcherrima Gilbert and Sebsebe.

PubMed

Teka, Tekleab; Bisrat, Daniel; Yeshak, Mariamawit Yonathan; Asres, Kaleab

2016-10-28

Malaria is one of the three major global public health threats due to a wide spread resistance of the parasites to the standard antimalarial drugs. Considering this growing problem, the ethnomedicinal approach in the search for new antimalarial drugs from plant sources has proven to be more effective and inexpensive. The leaves of Aloe pulcherrima Gilbert and Sebsebe, an endemic Ethiopian plant, are locally used for the treatment of malaria and other infectious diseases. Application of the leaf latex of A. pulcherrima on preparative silica gel TLC led to the isolation of two C -glycosylated anthrones, identified as nataloin ( 1 ) and 7-hydroxyaloin ( 2 ) by spectroscopic techniques (UV, IR, ¹H- and 13 C-NMR, HR-ESIMS). Both the latex and isolated compounds displayed antimalarial activity in a dose-independent manner using a four-day suppressive test, with the highest percent suppression of 56.2% achieved at 200 mg/kg/day for 2 . The results indicate that both the leaf latex of A. pulcherrima and its two major constituents are endowed with antiplasmodial activities, which support the traditional use of the leaves of the plant for the treatment of malaria.

Physalins B and F, seco-steroids isolated from Physalis angulata L., strongly inhibit proliferation, ultrastructure and infectivity of Trypanosoma cruzi.

PubMed

Meira, Cássio S; Guimarães, Elisalva T; Bastos, Tanira M; Moreira, Diogo R M; Tomassini, Therezinha C B; Ribeiro, Ivone M; Dos Santos, Ricardo R; Soares, Milena B P

2013-12-01

We previously observed that physalins have immunomodulatory properties, as well as antileishmanial and antiplasmodial activities. Here, we investigated the anti-Trypanosoma cruzi activity of physalins B, D, F and G. We found that physalins B and F were the most potent compounds against trypomastigote and epimastigote forms of T. cruzi. Electron microscopy of trypomastigotes incubated with physalin B showed disruption of kinetoplast, alterations in Golgi apparatus and endoplasmic reticulum, followed by the formation of myelin-like figures, which were stained with MDC to confirm their autophagic vacuole identity. Physalin B-mediated alteration in Golgi apparatus was likely due to T. cruzi protease perturbation; however physalins did not inhibit activity of the trypanosomal protease cruzain. Flow cytometry examination showed that cell death is mainly caused by necrosis. Treatment with physalins reduced the invasion process, as well as intracellular parasite development in macrophage cell culture, with a potency similar to benznidazole. We observed that a combination of physalins and benznidazole has a greater anti-T. cruzi activity than when compounds were used alone. These results indicate that physalins, specifically B and F, are potent and selective trypanocidal agents. They cause structural alterations and induce autophagy, which ultimately lead to parasite cell death by a necrotic process.

Caesalpinia bonduc serine proteinase inhibitor CbTI-2: Exploring the conformational features and antimalarial activity.

PubMed

Bhattacharyya, Arindam; Babu, C R

2017-10-01

Seeds of tropical legumes posses a repertoire of proteinase inhibitors (PI) and the current study highlights some structural/functional features of a strong serine PI from the seeds of Caesalpinia bonduc (CbTI-2). Following purification, N-terminal sequence of CbTI-2 revealed over 40% similarity with a few serine PIs of Caesalpinioideae subfamily. Upon exposure to metal ions and ionic/non ionic surfactants, CbTI-2 showed immense variation in the levels of antitryptic activity. Exposure of CbTI-2 to 1,4-Dithiothreitol, Guanidinium HCl, H 2 O 2 and Dimethyl sulfoxide led to a steady loss of inhibitory activity. Chemical modification of amino acids suggested an arginine as the active site residue. Circular Dichroism spectrum of native CbTI-2 revealed an unordered state. Secondary structure composition of CbTI-2 following exposure to extreme conditions (heat, acidic/alkaline environment, Guanidine hydrochloride and DTT) showed considerable perturbations that caused severe loss of antiproteolytic activity. DLS studies yielded a hydrodynamic radius of ∼2.2nm for CbTI-2 and also reconfirmed 1:1 stoichiometry for the trypsin-CbTI-2 complex. Initial studies indicated CbTI-2 to be a potent antiplasmodial agent by being highly toxic towards growth, schizont rupture process and erythrocytic invasion of Plasmodium falciparum. Copyright © 2017 Elsevier B.V. All rights reserved.

Four anti-protozoal and anti-bacterial compounds from Tapirira guianensis.

PubMed

Roumy, Vincent; Fabre, Nicolas; Portet, Bénédicte; Bourdy, Geneviève; Acebey, Lucia; Vigor, Claire; Valentin, Alexis; Moulis, Claude

2009-01-01

Tapirira guianensis is a common tree used in traditional medicine in French Guiana against several infectious diseases (malaria, leishmaniasis, bacteria, etc.). The bioassay-guided purification of CH(2)Cl(2) bark extract led to the isolation of four cyclic alkyl polyol derivatives: 4,6,2'-trihydroxy-6-[10'(Z)-heptadecenyl]-1-cyclohexen-2-one (1a), 1,4,6-trihydroxy-1,2'-epoxy-6-[10'(Z)-heptadecenyl]-2-cyclohexene (1b), 1,4,5,2'-tetrahydroxy-1-[10'(Z)-heptadecenyl]-2-cyclohexene (2), and 1,3,4,6-tetrahydroxy-1,2'-epoxy-6-[10'(Z)-heptadecenyl]-cyclohexane (3). The structures were established on the basis of 1D and 2D NMR analyses. The anti-leishmanial, anti-plasmodial, anti-bacterial (on Staphylococcus aureus, Staphylococcus epidermidis and Escherichia coli), and anti-fungal (on Candida albicans) activities of the extracts and of these original compounds were evaluated. Two showed medicinal interest supporting the traditional uses of the plant. The structures were established through spectral analyses of the isolates and their derivatives.

In vitro antiplasmodial activity, cytotoxicity and chemical profiles of sponge species of Cuban coasts.

PubMed

Mendiola, Judith; Regalado, Erik L; Díaz-García, Alexis; Thomas, Olivier P; Fernández-Calienes, Aymé; Rodríguez, Hermis; Laguna, Abilio; Valdés, Olga

2014-01-01

Aqueous and organic fractions from the crude extracts of 17 sponge species collected at Boca de Calderas, Havana, Cuba were analysed. The organic fractions of Mycale laxissima, Clathria echinata and Agelas cerebrum exhibited values of concentrations causing 50% inhibition of in vitro growth of Plasmodium berghei (IC50) of 42.3 ± 5.1, 52 ± 9.7 and 60.3 ± 10.6 μg/mL, respectively, while their selectivity indexes for fibroblast cell lines were 9.45, 4.24 and 8.7, correspondingly. These fractions reduced parasitemia of infected Balb/c mice as well. Selective cytotoxicity indexes against tumour HeLa cells focused an interest on the aqueous fraction of M. laxissima (>7.12) and organic fractions of Polymastia nigra (5.95), A. cerebrum (5.48) and Niphates erecta (>4.2). Triterpenoids/steroids and alkaloids detected in the organic fractions of M. laxissima, C. echinata and A. cerebrum should be isolated for future investigation.

In Vitro and In Vivo Antimalarial Evaluations of Myrtle Extract, a Plant Traditionally Used for Treatment of Parasitic Disorders

PubMed Central

Naghibi, Farzaneh; Esmaeili, Somayeh; Abdullah, Noor Rain; Nateghpour, Mehdi; Taghvai, Mahdieh; Kamkar, Siamak; Mosaddegh, Mahmoud

2013-01-01

Based on the collected ethnobotanical data from the Traditional Medicine and Materia Medica Research Center (TMRC), Iran, Myrtus communis L. (myrtle) was selected for the assessment of in vitro and in vivo antimalarial and cytotoxic activities. Methanolic extract of myrtle was prepared from the aerial parts and assessed for antiplasmodial activity, using the parasite lactate dehydrogenase (pLDH) assay against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) strains of Plasmodium falciparum. The 4-day suppressive test was employed to determine the parasitemia suppression of the myrtle extract against P. berghei   in vivo. The IC50 values of myrtle extract were 35.44 µg/ml against K1 and 0.87 µg/ml against 3D7. Myrtle extract showed a significant suppression of parasitaemia (84.8 ± 1.1% at 10 mg/kg/day) in mice infected with P. berghei after 4 days of treatment. Cytotoxic activity was carried out against mammalian cell lines using methyl thiazol tetrazolium (MTT) assay. No cytotoxic effect on mammalian cell lines up to 100 µg/mL was shown. The results support the traditional use of myrtle in malaria. Phytochemical investigation and understanding the mechanism of action would be in our upcoming project. PMID:24455686

Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice.

PubMed

Melariri, Paula; Kalombo, Lonji; Nkuna, Patric; Dube, Admire; Hayeshi, Rose; Ogutu, Benhards; Gibhard, Liezl; deKock, Carmen; Smith, Peter; Wiesner, Lubbe; Swai, Hulda

2015-01-01

Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity.

Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice

PubMed Central

Melariri, Paula; Kalombo, Lonji; Nkuna, Patric; Dube, Admire; Hayeshi, Rose; Ogutu, Benhards; Gibhard, Liezl; deKock, Carmen; Smith, Peter; Wiesner, Lubbe; Swai, Hulda

2015-01-01

Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity. PMID:25759576

A New Alkamide with an Endoperoxide Structure from Acmella ciliata (Asteraceae) and Its in Vitro Antiplasmodial Activity.

PubMed

Silveira, Narjara; Saar, Julia; Santos, Alan Diego C; Barison, Andersson; Sandjo, Louis P; Kaiser, Marcel; Schmidt, Thomas J; Biavatti, Maique W

2016-06-11

From the aerial parts of Acmella ciliata (H.B.K.) Cassini (basionym Spilanthes ciliata Kunth; Asteraceae), three alkamides were isolated and identified by mass- and NMR spectroscopic methods as (2E,6E,8E)-N-isobutyl-2,6,8-decatrienamide (spilanthol, (1)), N-(2-phenethyl)-2E-en-6,8-nonadiynamide (2) and (2E,7Z)-6,9-endoperoxy-N-isobutyl-2,7-decadienamide (3). While 1 and 2 are known alkamides, compound 3 has not been described until now. It was found that the unusual cyclic peroxide 3 exists as a racemate of both enantiomers of each alkamide; the 6,9-cis- as well as the 6,9-trans-configured diastereomers, the former represents the major, the latter the minor constituent of the mixture. In vitro tests for activity against the human pathogenic parasites Trypanosoma brucei rhodesiense and Plasmodium falciparum revealed that 1 and 3 possess activity against the NF54 strain of the latter (IC50 values of 4.5 and 5.1 µM, respectively) while 2 was almost inactive. Compound 3 was also tested against multiresistant P. falciparum K1 and was found to be even more active against this parasite strain (IC50 = 2.1 µM) with considerable selectivity (IC50 against L6 rat skeletal myoblasts = 168 µM).

Structure-activity relationships of mononuclear metal-thiosemicarbazone complexes endowed with potent antiplasmodial and antiamoebic activities.

PubMed

Bahl, Deepa; Athar, Fareeda; Soares, Milena Botelho Pereira; de Sá, Matheus Santos; Moreira, Diogo Rodrigo Magalhães; Srivastava, Rajendra Mohan; Leite, Ana Cristina Lima; Azam, Amir

2010-09-15

A useful concept for the rational design of antiparasitic drug candidates is the complexation of bioactive ligands with transition metals. In view of this, an investigation was conducted into a new set of metal complexes as potential antiplasmodium and antiamoebic agents, in order to examine the importance of metallic atoms, as well as the kind of sphere of co-ordination, in these biological properties. Four functionalized furyl-thiosemicarbazones (NT1-4) treated with divalent metals (Cu, Co, Pt, and Pd) to form the mononuclear metallic complexes of formula [M(L)2Cl2] or [M(L)Cl2] were examined. The pharmacological characterization, including assays against Plasmodium falciparum and Entamoeba histolytica, cytotoxicity to mammalian cells, and interaction with pBR 322 plasmid DNA was performed. Structure-activity relationship data revealed that the metallic complexation plays an essential role in antiprotozoal activity, rather than the simple presence of the ligand or metal alone. Important steps towards identification of novel antiplasmodium (NT1Cu, IC50 of 4.6 microM) and antiamoebic (NT2Pd, IC50 of 0.6 microM) drug prototypes were achieved. Of particular relevance to this work, these prototypes were able to reduce the proliferation of these parasites at concentrations that are not cytotoxic to mammalian cells. Copyright (c) 2010. Published by Elsevier Ltd.

Biological characterization of the Amazon coral Micrurus spixii snake venom: Isolation of a new neurotoxic phospholipase A2.

PubMed

Terra, Angelo L C; Moreira-Dill, Leandro S; Simões-Silva, Rodrigo; Monteiro, José Roniele N; Cavalcante, Walter L G; Gallacci, Márcia; Barros, Neuza B; Nicolete, Roberto; Teles, Carolina B G; Medeiros, Patrícia S M; Zanchi, Fernando B; Zuliani, Juliana P; Calderon, Leonardo A; Stábeli, Rodrigo G; Soares, Andreimar M

2015-09-01

The Micrurus genus is the American representative of Elapidae family. Micrurus spixii is endemic of South America and northern states of Brazil. Elapidic venoms contain neurotoxins that promote curare-mimetic neuromuscular blockage. In this study, biochemical and functional characterizations of M. spixii crude venom were performed and a new neurotoxic phospholipase A2 called MsPLA2-I was isolated. M. spixii crude venom caused severe swelling in the legs of tested mice and significant release of creatine kinase (CK) showing its myotoxic activity. Leishmanicidal activity against Leishmania amazonensis (IC50 1.24 μg/mL) was also observed, along with antiplasmodial activity against Plasmodium falciparum, which are unprecedented for Micrurus venoms. MsPLA2-I with a Mr 12,809.4 Da was isolated from the crude venom of M. spixii. The N-terminal sequencing of a fragment of 60 amino acids showed 80% similarity with another PLA2 from Micrurus altirostris. This toxin and the crude venom showed phospholipase activity. In a mouse phrenic nerve-diaphragm preparation, M. spixii venom and MsPLA2-I induced the blockage of both direct and indirect twitches. While the venom presented a pronounced myotoxic activity, MsPLA2-I expressed a summation of neurotoxic activity. The results of this study make M. spixii crude venom promising compounds in the exploration of molecules with microbicidal potential. Copyright © 2015 Elsevier Ltd. All rights reserved.

Activity of Ocimum basilicum, Ocimum canum, and Cymbopogon citratus essential oils against Plasmodium falciparum and mature-stage larvae of Anopheles funestus s.s.

PubMed

Akono Ntonga, Patrick; Baldovini, Nicolas; Mouray, Elisabeth; Mambu, Lengo; Belong, Philippe; Grellier, Philippe

2014-01-01

The biological activities of essential oils from three plants grown in Cameroon: Ocimum basilicum, Ocimum canum, and Cymbopogon citratus were tested against Plasmodium falciparum and mature-stage larvae of Anopheles funestus. Gas chromatography and gas chromatography - mass spectrometry analyses showed that the main compounds are geranial, 1,8-cineole and linalool in C. citratus, O. canum and O. basilicum, respectively. Larvicidal tests carried out according to the protocol recommended by the World Health Organization showed that the essential oil of leaves of C. citratus is the most active against larvae of An. funestus (LC50 values = 35.5 ppm and 34.6 ppm, respectively, for larval stages III and IV after 6 h of exposure). Besides, the in vitro anti-plasmodial activity evaluated by the radioisotopic method showed that the C. citratus oil is the most active against P. falciparum, with an IC50 value of 4.2 ± 0.5 μg/mL compared with O. canum (20.6 ± 3.4 μg/mL) and O. basilicum (21 ± 4.6 μg/mL). These essential oils can be recommended for the development of natural biocides for fighting the larvae of malaria vectors and for the isolation of natural products with anti-malarial activity. © P. Akono Ntonga et al., published by EDP Sciences, 2014.

Activity of Ocimum basilicum, Ocimum canum, and Cymbopogon citratus essential oils against Plasmodium falciparum and mature-stage larvae of Anopheles funestus s.s.

PubMed Central

Akono Ntonga, Patrick; Baldovini, Nicolas; Mouray, Elisabeth; Mambu, Lengo; Belong, Philippe; Grellier, Philippe

2014-01-01

The biological activities of essential oils from three plants grown in Cameroon: Ocimum basilicum, Ocimum canum, and Cymbopogon citratus were tested against Plasmodium falciparum and mature-stage larvae of Anopheles funestus. Gas chromatography and gas chromatography – mass spectrometry analyses showed that the main compounds are geranial, 1,8-cineole and linalool in C. citratus, O. canum and O. basilicum, respectively. Larvicidal tests carried out according to the protocol recommended by the World Health Organization showed that the essential oil of leaves of C. citratus is the most active against larvae of An. funestus (LC50 values = 35.5 ppm and 34.6 ppm, respectively, for larval stages III and IV after 6 h of exposure). Besides, the in vitro anti-plasmodial activity evaluated by the radioisotopic method showed that the C. citratus oil is the most active against P. falciparum, with an IC50 value of 4.2 ± 0.5 μg/mL compared with O. canum (20.6 ± 3.4 μg/mL) and O. basilicum (21 ± 4.6 μg/mL). These essential oils can be recommended for the development of natural biocides for fighting the larvae of malaria vectors and for the isolation of natural products with anti-malarial activity. PMID:24995776

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites.

PubMed

Ehrhardt, Katharina; Deregnaucourt, Christiane; Goetz, Alice-Anne; Tzanova, Tzvetomira; Gallo, Valentina; Arese, Paolo; Pradines, Bruno; Adjalley, Sophie H; Bagrel, Denyse; Blandin, Stephanie; Lanzer, Michael; Davioud-Charvet, Elisabeth

2016-09-01

Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

PubMed Central

Ehrhardt, Katharina; Deregnaucourt, Christiane; Goetz, Alice-Anne; Tzanova, Tzvetomira; Gallo, Valentina; Arese, Paolo; Pradines, Bruno; Adjalley, Sophie H.; Bagrel, Denyse; Blandin, Stephanie; Lanzer, Michael

2016-01-01

Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers—a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum. We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents. PMID:27297478

Synthesis, β-haematin inhibition, and in vitro antimalarial testing of isocryptolepine analogues: SAR study of indolo[3,2-c]quinolines with various substituents at C2, C6, and N11.

PubMed

Wang, Ning; Wicht, Kathryn J; Imai, Kento; Wang, Ming-Qi; Anh Ngoc, Tran; Kiguchi, Ryo; Kaiser, Marcel; Egan, Timothy J; Inokuchi, Tsutomu

2014-05-01

A series of indolo[3,2-c]quinolines were synthesized by modifying the side chains of the ω-aminoalkylamines at the C6 position and introducing substituents at the C2 position, such as F, Cl, Br, Me, MeO and NO2, and a methyl group at the N11 position for an SAR study. The in vitro antiplasmodial activities of the derivative agents against two different strains (CQS: NF54 and CQR: K1) and the cytotoxic activity against normal L6 cells were evaluated. The test results showed that compounds 6k and 6l containing the branched methyl groups of 3-aminopropylamino at C6 with a Cl atom at C2 exhibited a very low cytotoxicity with IC50 values above 4000 nM, high antimalarial activities with IC50 values of about 11 nM for CQS (NF54), IC50 values of about 17 nM for CQR (K1), and RI resistance indices of 1.6. Furthermore, the compounds were tested for β-haematic inhibition, and QSAR revealed an interesting linear correlation between the biological activity of CQS (NF54) and three contributing factors, namely solubility, hydrophilic surface area, and β-haematin inhibition for this series. In vivo testing of 6l showed a reduction in parasitaemia on day 4 with an activity of 38%. Copyright © 2014 Elsevier Ltd. All rights reserved.

Lippia javanica (Burm.f.) Spreng.: Traditional and Commercial Uses and Phytochemical and Pharmacological Significance in the African and Indian Subcontinent

PubMed Central

2017-01-01

Lippia javanica occurs naturally in central, eastern, and southern Africa and has also been recorded in the tropical Indian subcontinent. The potential of L. javanica as herbal or recreational tea and herbal medicine and its associated phytochemistry and biological properties are reviewed. The extensive literature survey revealed that L. javanica is used as herbal tea and has ethnomedicinal applications such as in colds, cough, fever, malaria, wounds, diarrhoea, chest pains, bronchitis, and asthma. Multiple classes of phytochemicals including volatile and nonvolatile secondary metabolites such as alkaloids, amino acids, flavonoids, iridoids, and triterpenes as well as several minerals have been identified from L. javanica. Scientific studies on L. javanica indicate that it has a wide range of pharmacological activities which include anticancer, antiamoebic, antidiabetic, antimalarial, antimicrobial, antioxidant, antiplasmodial, and pesticidal effects. Although many of the traditional uses of L. javanica have been validated by phytochemical and pharmacological studies, there are still some gaps where current knowledge could be improved. Lippia javanica is popular as both herbal and recreational tea, but there is need for more precise studies to evaluate the safety and clinical value of its main active crude and pure compounds and to clarify their mechanisms of action. PMID:28115974

A new protoberberine alkaloid from Meconopsis simplicifolia (D. Don) Walpers with potent antimalarial activity against a multidrug resistant Plasmodium falciparum strain.

PubMed

Wangchuk, Phurpa; Phurpa, Wangchuk; Keller, Paul A; Pyne, Stephen G; Lie, Wilford; Willis, Anthony C; Rattanajak, Roonglawan; Kamchonwongpaisan, Sumalee

2013-12-12

The aerial components of Meconopsis simplicifolia (D. Don) Walpers are indicated in Bhutanese traditional medicine for treating malaria, coughs and colds, and the infections of the liver, lung and blood. This study is to validate the ethnopharmacological uses of this plant and also identify potent antimalarial drug leads through bioassays of its crude extracts and phytochemical constituents. Meconopsis simplicifolia (D. Don) Walpers was collected from Bhutan and its crude MeOH extract was subjected to acid-base fractionation. Through repeated extractions, separations and spectroscopic analysis, the alkaloids obtained were identified and tested for their antimalarial and cytotoxicity activities. Phytochemical studies resulted in the isolation of one new protoberberine type alkaloid which we named as simplicifolianine and five known alkaloids: protopine, norsanguinarine, dihydrosanguinarine, 6-methoxydihydrosanguinarine and oxysanguinarine. Among the five of the alkaloids tested, simplicifolianine showed the most potent antiplasmodial activities against the Plasmodium falciparum strains, TM4/8.2 (chloroquine-antifolate sensitive strain) and K1CB1 (multidrug resistant strain) with IC50 values of 0.78 μg/mL and 1.29 μg/mL, respectively. The compounds tested did not show any significant cytotoxicity activities against human oral carcinoma KB cells and normal Vero cells of African kidney epithelial cells. This study validated the traditional uses of the plant for the treatment of malaria and identified a new alkaloid, simplicifolianine as a potential antimalarial drug lead. © 2013 Published by Elsevier Ireland Ltd.

Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery.

PubMed

Quiliano, Miguel; Pabón, Adriana; Moles, Ernest; Bonilla-Ramirez, Leonardo; Fabing, Isabelle; Fong, Kim Y; Nieto-Aco, Diego A; Wright, David W; Pizarro, Juan C; Vettorazzi, Ariane; López de Cerain, Adela; Deharo, Eric; Fernández-Busquets, Xavier; Garavito, Giovanny; Aldana, Ignacio; Galiano, Silvia

2018-05-25

Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70-73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70-73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC 50 s < 0.28 μM), and compounds 55, 56, 64, 70, 71, and 72 showed potent biological activity in chloroquine-sensitive and multidrug-resistant strains (IC 50 s < 0.7 μM for 3D7, D6, FCR-3 and C235). All of these compounds share appropriate drug-likeness profiles and adequate selectivity indexes (77 < SI < 184) as well as lack genotoxicity. In vivo efficacy tests in a mouse model showed compounds 66 and 72 to be promising candidates as they exhibited significant parasitemia reductions of 96.4% and 80.4%, respectively. Additional studies such as liver stage and sporogony inhibition, target exploration of heat shock protein 90 of P. falciparum, targeted delivery by immunoliposomes, and enantiomer characterization were performed and strongly reinforce the hypothesis of 1-aryl-3-substituted propanol derivatives as promising antimalarial compounds. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Structure-based design synthesis of functionalized 3-(5-(s-phenyl)-4H-pyrazol-3-yl)-2H-chromen-2-one motifs and indigenous plant extracts and their antimalarial potential

NASA Astrophysics Data System (ADS)

Olayinka, Ajani; Grace, Olasehinde; Titilope, Dokunmu; Ruth, Diji-Geske; Olabode, Onileere; John, Openibo; Oreoluwa, Oluseye; Tochukwu, Chileke; Ezekiel, Adebiyi

2018-04-01

Resistance of the malaria parasite to conventional therapeutic agents calls for increased efforts in antimalarial drug discovery. Current efforts should be targeted at developing safe and affordable new agents to counter the spread of malaria parasites that are resistant to existing therapy. In this study, toxicological and in vivo antiplasmodial properties of 3-(5-(s-phenyl)-4H-pyrazol-3-yl)-42H-chromen-2, Mangifera indica and Tithonia diversifolia in swiss albino mice models, Musmusculus were investigated. 2H-Chromen-2-one also known as coumarin is highly privileged oxygen-containing heterocyclic entity which are present in plant kingdom as secondary metabolites. The maceration technique of crude drug extraction was employed using cold water extraction. Toxicological analysis was carried out using Lorke's method for acute toxicity testing while the chemosuppressive activity was carried out using Peter's four day test on early infection. We also report the synthesis of functionalized 3-(5-(s-phenyl)-4H-pyrazol-3-yl)-2H-chromen-2-one motifs via microwave assisted synthetic approach and isolation of indigenous plant extract in order to investigate their antimalarial efficacy. The condensation reaction of 3-acetylcoumarin with various benzaldehyde derivatives resulted in the formation of 3-[3-acryloyl]-2H-chromen-2-one which was subsequently reaction the hydrazine hydrate via microwave assisted hydrazinolysis to afford the targeted 3-(5-(s-phenyl)-4H-pyrazol-3-yl)-2H-chromen-2-one motifs. The chemical structures were confirmed by analytical data and spectroscopic means such as FT-IR, UV, 1H NMR, 13C NMR and DEPT-135. The microwave assisted reaction was remarkably successful and gave targeted 3-(5-(s-phenyl)-4H-pyrazol-3-yl)-2H-chromen-2-one motifs in higher yields at lesser reaction time compared to conventional heating method. The LD50 of the aqueous extracts of the leaves and stem bark Mangifera indica was established to be ± 707.11 mg/kg b.w., p.o. (body weight, administered orally) in mice. Tithonia diversifolia aqueous leaf extracts is non-toxic at doses as high as 1000 mg/kg while the LD50 of the ethanolic leaf extracts was established to be ± 707.11 mg/kg b.w., p.o. in mice. The in vivo antiplasmodial activity was studied in chloroquine-sensitive Plasmodium berghei berghei - NK65 infected mice. All the plant extracts, at the doses (100, 200 and 400 mg/kg b.w., p.o.) used, produced significant (p < 0.05), dose dependent activity (> 80% inhibition of parasitaemia at maximum dose) against the parasite in the suppressive tests. The in vitro antimalarial screening of the synthesized compounds is presently on-going and the finding will be reported in due course.

Machine learning prioritizes synthesis of primaquine ureidoamides with high antimalarial activity and attenuated cytotoxicity.

PubMed

Levatić, Jurica; Pavić, Kristina; Perković, Ivana; Uzelac, Lidija; Ester, Katja; Kralj, Marijeta; Kaiser, Marcel; Rottmann, Matthias; Supek, Fran; Zorc, Branka

2018-02-25

Primaquine (PQ) is a commonly used drug that can prevent the transmission of Plasmodium falciparum malaria, however toxicity limits its use. We prepared five groups of PQ derivatives: amides 1a-k, ureas 2a-k, semicarbazides 3a,b, acylsemicarbazides 4a-k and bis-ureas 5a-v, and evaluated them for antimalarial activity in vitro against the erythrocytic stage of P. falciparum NF54. Particular substituents, such as trityl (in 2j and 5r) and methoxybenzhydryl (in 3b and 5v) were associated with a favorable cytotoxicity-to-activity ratio. To systematically link structural features of PQ derivatives to antiplasmodial activity, we performed a quantitative structure-activity relationship (QSAR) study using the Support Vector Machines machine learning method. This yielded a highly accurate statistical model (R 2  = 0.776 in cross-validation), which was used to prioritize novel candidate compounds. Seven novel PQ-ureidoamides 10a-g were synthesized and evaluated for activity, highlighting the benzhydryl ureidoamides 10e and 10f derived from p-chlorophenylglycine. Further experiments on human cell lines revealed that 10e and 10f are an order of magnitude less toxic than PQ in vitro while having antimalarial activity indistinguishable from PQ. The toxicity profile of novel compounds 10 toward human cells was particularly favorable when the glucose-6-phosphate dehydrogenase (G6PD) was inhibited, while toxicity of PQ was exacerbated by G6PD inhibition. Our work therefore highlights promising lead compounds for the development of effective antimalarial drugs that may also be safer for G6PD-deficient patients. In addition, we provide computational inferences of antimalarial activity and cytotoxicity for thousands of PQ-like molecular structures. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Recombinant Scorpine Produced Using SUMO Fusion Partner in Escherichia coli Has the Activities against Clinically Isolated Bacteria and Inhibits the Plasmodium falciparum Parasitemia In Vitro

PubMed Central

Gu, Yaping; Zhou, Huayun; Cao, Jun; Gao, Qi

2014-01-01

Scorpine, a small cationic peptide from the venom of Pandinus imperator, which has been shown to have anti-bacterial and anti-plasmodial activities, has potential important applications in the pharmaceutical industries. However, the isolation of scorpine from natural sources is inefficient and time-consuming. Here, we first report the expression and purification of recombinant scorpine in Escherichia coli, using small ubiquitin-related modifier (SUMO) fusion partner. The fusion protein was expressed in soluble form in E. coli, and expression was verified by SDS-PAGE and western blotting analysis. The fusion protein was purified to 90% purity by nickel–nitrilotriacetic acid (Ni2+–NTA) resin chromatography. After the SUMO-scorpine fusion protein was cleaved by the SUMO protease, the cleaved sample was reapplied to a Ni2+–NTA column. Tricine/SDS-PAGE gel results indicated that Scorpine had been purified successfully to more than 95% purity. The recombinantly expressed Scorpine showed anti-bacterial activity against two standard bacteria including Staphylococcus aureus ATCC 29213 and Acinetobacter baumannii ATCC 19606, and clinically isolated bacteria including S. aureus S, S. aureus R, A. baumannii S, and A. baumannii R. It also produced 100% reduction in Plasmodium falciparum parasitemia in vitro. Thus, the expression strategy presented in this study allowed convenient high yield and easy purification of recombinant Scorpine for pharmaceutical applications in the future. PMID:25068263

B and T lymphocyte attenuator restricts the protective immune response against experimental malaria.

PubMed

Adler, Guido; Steeg, Christiane; Pfeffer, Klaus; Murphy, Theresa L; Murphy, Kenneth M; Langhorne, Jean; Jacobs, Thomas

2011-11-15

The immune response against the blood stage of malaria has to be tightly regulated to allow for vigorous antiplasmodial activity while restraining potentially lethal immunopathologic damage to the host like cerebral malaria. Coinhibitory cell surface receptors are important modulators of immune activation. B and T lymphocyte attenuator (BTLA) (CD272) is a coinhibitory receptor expressed by most leukocytes, with the highest expression levels on T and B cells, and is involved in the maintenance of peripheral tolerance by dampening the activation of lymphocytes. The function of BTLA is described in several models of inflammatory disorders and autoimmunity, but its function in infectious diseases is less well characterized. Also, little is known about the influence of BTLA on non-T cells. In this study, we analyzed the function of BTLA during blood-stage malaria infection with the nonlethal Plasmodium yoelii strain 17NL. We show that BTLA knockout mice exhibit strongly reduced parasitemia and clear the infection earlier compared with wild-type mice. This increased resistance was seen before the onset of adaptive immune mechanisms and even in the absence of T and B cells but was more pronounced at later time points when activation of T and B cells was observed. We demonstrate that BTLA regulates production of proinflammatory cytokines in a T cell-intrinsic way and B cell intrinsically regulates the production of P. yoelii 17NL-specific Abs. These results indicate that the coinhibitory receptor BTLA plays a critical role during experimental malaria and attenuates the innate as well as the subsequent adaptive immune response.

Green synthesized nanoparticles in the fight against mosquito-borne diseases and cancer-a brief review.

PubMed

Benelli, Giovanni

2016-12-01

Nanobiomedicine and parasitology are facing a number of key challenges, which mostly deal with the paucity of effective preventive and curative tools against mosquito-borne diseases and cancer. In this scenario, the employ of botanical and invertebrate extracts as reducing, stabilizing and capping agents for the synthesis of nanoparticles is advantageous over chemical and physical methods, since it is one-pot, cheap, and does not require high pressure, energy, temperature, or the use of highly toxic chemicals. Considering the overlooked connection between mosquito vector activity and the spread of cancer in USA, this review focused on the current knowledge available about green synthesized nanoparticles with efficacy against mosquito-borne diseases and cancer. Green fabricated metal nanoparticles showed antiplasmodial activity that often encompasses the efficacy of currently marked drugs for malaria treatment. They have been also reported as growth inhibitors against dengue virus (serotype DEN-2), with moderate cytotoxicity on mammalian cells. However, this feature is strongly dependent to the botanical agents employed during nanosynthesis. In addition, green nanoparticles have been successfully used to reduce mosquito young instar populations in the field. The final section focuses on some issues for future research, with special reference to the chemical standardization of the botanical extracts used for nanosynthesis and the potential effects on green fabricated nanoparticles on non-target organisms. Copyright © 2016 Elsevier Inc. All rights reserved.

Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

PubMed Central

Ma, Yufan; Lu, Tingli; Zhao, Wen; Wang, Ying; Chen, Ting; Mei, Qibing

2014-01-01

Artemether and lumefantrine (also known as benflumetol) are difficult to formulate for parenteral administration because of their low aqueous solubility. Cremophor EL as an emulsion excipient has been shown to cause serious side effects. This study reports a method of preparation and the therapeutic efficacies of novel lipid emulsion (LE) delivery systems with artemether, lumefantrine, or artemether in combination with lumefantrine, for parenteral administration. Their physical and chemical stabilities were also evaluated. Furthermore, the in vivo antimalarial activities of the lipid emulsions developed were tested in Plasmodium berghei-infected mice. Artemether, lumefantrine, or artemether in combination with lumefantrine was encapsulated in an oil phase, and the in vivo performance was assessed by comparison with artesunate for injection. It was found that the lumefantrine lipid emulsion (LUM-LE) and artemether-lumefantrine lipid emulsion (ARM-LUM-LE-3) (1:6) began to decrease the parasitemia levels after only 3 days, and the parasitemia inhibition was 90% at doses of 0.32 and 0.27 mg/kg, respectively, with immediate antimalarial effects greater than those of the positive-control group and constant antimalarial effects over 30 days. LUM-LE and ARM-LUM-LE-3 demonstrated the best performance in terms of chemical and physical stabilities and antiplasmodial efficacy, with a mean particle size of 150 nm, and they have many favorable properties for parenteral administration, such as biocompatibility, physical stability, and ease of preparation. PMID:24982079

Antiplasmodial Activity and Mechanism of Action of RSM-932A, a Promising Synergistic Inhibitor of Plasmodium falciparum Choline Kinase

PubMed Central

Zimmerman, Tahl; Moneriz, Carlos; Diez, Amalia; Bautista, José Manuel; Gómez del Pulgar, Teresa; Cebrián, Arancha

2013-01-01

We have investigated the mechanism of action of inhibition of the choline kinase of P. falciparum (p.f.-ChoK) by two inhibitors of the human ChoKα, MN58b and RSM-932A, which have previously been shown to be potent antitumoral agents. The efficacy of these inhibitors against p.f.-ChoK is investigated using enzymatic and in vitro assays. While MN58b may enter the choline/phosphocholine binding site, RSM-932A appears to have an altogether novel mechanism of inhibition and is synergistic with respect to both choline and ATP. A model of inhibition for RSM-932A in which this inhibitor traps p.f.-ChoK in a phosphorylated intermediate state blocking phosphate transfer to choline is presented. Importantly, MN58b and RSM-932A have in vitro inhibitory activity in the low nanomolar range and are equally effective against chloroquine-sensitive and chloroquine-resistant strains. RSM-932A and MN58b significantly reduced parasitemia and induced the accumulation of trophozoites and schizonts, blocking intraerythrocytic development and interfering with parasite egress or invasion, suggesting a delay of the parasite maturation stage. The present data provide two new potent structures for the development of antimalarial compounds and validate p.f.-ChoK as an accessible drug target against the parasite. PMID:24041883

Phyllanthus amarus: ethnomedicinal uses, phytochemistry and pharmacology: a review.

PubMed

Patel, Jay Ram; Tripathi, Priyanka; Sharma, Vikas; Chauhan, Nagendra Singh; Dixit, Vinod Kumar

2011-11-18

Phyllanthus amarus Schum. & Thonn. belongs to the family Euphorbiaceae is a small herb well known for its medicinal properties and widely used worldwide. P. amarus is an important plant of Indian Ayurvedic system of medicine which is used in the problems of stomach, genitourinary system, liver, kidney and spleen. It is bitter, astringent, stomachic, diuretic, febrifuge and antiseptic. The whole plant is used in gonorrhea, menorrhagia and other genital affections. It is useful in gastropathy, diarrhoea, dysentery, intermittent fevers, ophthalmopathy, scabies, ulcers and wounds. The present review covers a literature across from 1980 to 2011. Some information collected from traditional Ayurvedic texts and published literature on ethanomedicinal uses of Phyllanthus amarus in different countries worldwide. Phytochemical studies have shown the presence of many valuable compounds such as lignans, flavonoids, hydrolysable tannins (ellagitannins), polyphenols, triterpenes, sterols and alkaloids. The extracts and the compounds isolated from P. amarus show a wide spectrum of pharmacological activities including antiviral, antibacterial, antiplasmodial, anti-inflammatory, antimalarial, antimicrobial, anticancer, antidiabetic, hypolipidemic, antioxidant, hepatoprotective nephroprotective and diurectic properties. The present review summarizes information concerning the morphology, ecology, ethnopharmacology, phytochemistry, biological activities, clinical applications and toxicological reports of P. amarus. This review aims at gathering the research work undertaken till date on this plant in order to provide sufficient baseline information for future works and commercial exploitation. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Multipurpose effectiveness of Couroupita guianensis-synthesized gold nanoparticles: high antiplasmodial potential, field efficacy against malaria vectors and synergy with Aplocheilus lineatus predators.

PubMed

Subramaniam, Jayapal; Murugan, Kadarkarai; Panneerselvam, Chellasamy; Kovendan, Kalimuthu; Madhiyazhagan, Pari; Dinesh, Devakumar; Kumar, Palanisamy Mahesh; Chandramohan, Balamurugan; Suresh, Udaiyan; Rajaganesh, Rajapandian; Alsalhi, Mohamad Saleh; Devanesan, Sandhanasamy; Nicoletti, Marcello; Canale, Angelo; Benelli, Giovanni

2016-04-01

Mosquito-borne diseases represent a deadly threat for millions of people worldwide. According to recent estimates, about 3.2 billion people, almost half of the world's population, are at risk of malaria. Malaria control is particularly challenging due to a growing number of chloroquine-resistant Plasmodium and pesticide-resistant Anopheles vectors. Newer and safer control tools are required. In this research, gold nanoparticles (AuNPs) were biosynthesized using a cheap flower extract of Couroupita guianensis as reducing and stabilizing agent. The biofabrication of AuNP was confirmed by UV-vis spectrophotometry, Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), energy-dispersive X-ray (EDX) spectroscopy, X-ray diffraction (XRD), zeta potential, and particle size analysis. AuNP showed different shapes including spheres, ovals, and triangles. AuNPs were crystalline in nature with face-centered cubic geometry; mean size was 29.2-43.8 nm. In laboratory conditions, AuNPs were toxic against Anopheles stephensi larvae, pupae, and adults. LC50 was 17.36 ppm (larva I), 19.79 ppm (larva II), 21.69 ppm (larva III), 24.57 ppm (larva IV), 28.78 ppm (pupa), and 11.23 ppm (adult). In the field, a single treatment with C. guianensis flower extract and AuNP (10 × LC50) led to complete larval mortality after 72 h. In standard laboratory conditions, the predation efficiency of golden wonder killifish, Aplocheilus lineatus, against A. stephensi IV instar larvae was 56.38 %, while in an aquatic environment treated with sub-lethal doses of the flower extract or AuNP, predation efficiency was boosted to 83.98 and 98.04 %, respectively. Lastly, the antiplasmodial activity of C. guianensis flower extract and AuNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. IC50 of C. guianensis flower extract was 43.21 μg/ml (CQ-s) and 51.16 μg/ml (CQ-r). AuNP IC50 was 69.47 μg/ml (CQ-s) and 76.33 μg/ml (CQ-r). Overall, our results showed the multipurpose effectiveness of C. guianensis-synthesized AuNPs, since they may be proposed as newer and safer tools in the fight against CQ-r strains of P. falciparum and for field control of malaria vectors, in synergy with wonder killifish predators.

Ethnopharmacological Uses, Phytochemistry, and Pharmacological Properties of Croton macrostachyus Hochst. Ex Delile: A Comprehensive Review

PubMed Central

2017-01-01

Croton macrostachyus is widely used as herbal medicine by the indigenous people of tropical Africa. The potential of C. macrostachyus as herbal medicine, the phytochemistry, and pharmacological properties of its parts used as herbal medicines are reviewed. The extensive literature survey revealed that C. macrostachyus is traditionally used to treat or manage at least 81 human and animal diseases and ailments. The species is used as herbal medicine for diseases and ailments such as abdominal pains, cancer, gastrointestinal disorders, malaria, pneumonia, sexually transmitted infections, skin infections, typhoid, and wounds and as ethnoveterinary medicine. Multiple classes of phytochemicals such as alkaloids, amino acids, anthraquinones, carbohydrates, cardiac glycosides, coumarins, essential oil, fatty acids, flavonoids, phenolic compounds, phlobatannins, polyphenols, phytosteroides, saponins, sterols, tannins, terpenoids, unsaturated sterol, vitamin C, and withanoides have been isolated from the species. Pharmacological studies on C. macrostachyus indicate that it has a wide range of pharmacological activities such as anthelmintic, antibacterial, antimycobacterial, antidiarrhoeal, antifungal, anticonvulsant and sedative, antidiabetic, anti-inflammatory, antileishmanial, antioxidant, antiplasmodial, and larvicidal effects. Croton macrostachyus has potential as a possible source of a wide range of pharmaceutical products for the treatment of a wide range of both human and animal diseases and ailments. PMID:29234365

Fern-synthesized nanoparticles in the fight against malaria: LC/MS analysis of Pteridium aquilinum leaf extract and biosynthesis of silver nanoparticles with high mosquitocidal and antiplasmodial activity.

PubMed

Panneerselvam, Chellasamy; Murugan, Kadarkarai; Roni, Mathath; Aziz, Al Thabiani; Suresh, Udaiyan; Rajaganesh, Rajapandian; Madhiyazhagan, Pari; Subramaniam, Jayapal; Dinesh, Devakumar; Nicoletti, Marcello; Higuchi, Akon; Alarfaj, Abdullah A; Munusamy, Murugan A; Kumar, Suresh; Desneux, Nicolas; Benelli, Giovanni

2016-03-01

Malaria remains a major public health problem due to the emergence and spread of Plasmodium falciparum strains resistant to chloroquine. There is an urgent need to investigate new and effective sources of antimalarial drugs. This research proposed a novel method of fern-mediated synthesis of silver nanoparticles (AgNP) using a cheap plant extract of Pteridium aquilinum, acting as a reducing and capping agent. AgNP were characterized by UV-vis spectrophotometry, Fourier transform infrared (FTIR) spectroscopy, energy-dispersive X-ray spectroscopy (EDX), and X-ray diffraction (XRD). Phytochemical analysis of P. aquilinum leaf extract revealed the presence of phenols, alkaloids, tannins, flavonoids, proteins, carbohydrates, saponins, glycosides, steroids, and triterpenoids. LC/MS analysis identified at least 19 compounds, namely pterosin, hydroquinone, hydroxy-acetophenone, hydroxy-cinnamic acid, 5, 7-dihydroxy-4-methyl coumarin, trans-cinnamic acid, apiole, quercetin 3-glucoside, hydroxy-L-proline, hypaphorine, khellol glucoside, umbelliferose, violaxanthin, ergotamine tartrate, palmatine chloride, deacylgymnemic acid, methyl laurate, and palmitoyl acetate. In DPPH scavenging assays, the IC50 value of the P. aquilinum leaf extract was 10.04 μg/ml, while IC50 of BHT and rutin were 7.93 and 6.35 μg/ml. In mosquitocidal assays, LC50 of P. aquilinum leaf extract against Anopheles stephensi larvae and pupae were 220.44 ppm (larva I), 254.12 ppm (II), 302.32 ppm (III), 395.12 ppm (IV), and 502.20 ppm (pupa). LC50 of P. aquilinum-synthesized AgNP were 7.48 ppm (I), 10.68 ppm (II), 13.77 ppm (III), 18.45 ppm (IV), and 31.51 ppm (pupa). In the field, the application of P. aquilinum extract and AgNP (10 × LC50) led to 100 % larval reduction after 72 h. Both the P. aquilinum extract and AgNP reduced longevity and fecundity of An. stephensi adults. Smoke toxicity experiments conducted against An. stephensi adults showed that P. aquilinum leaf-, stem-, and root-based coils evoked mortality rates comparable to the permethrin-based positive control (57, 50, 41, and 49 %, respectively). Furthermore, the antiplasmodial activity of P. aquilinum leaf extract and green-synthesized AgNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of P. falciparum. IC50 of P. aquilinum were 62.04 μg/ml (CQ-s) and 71.16 μg/ml (CQ-r); P. aquilinum-synthesized AgNP achieved IC50 of 78.12 μg/ml (CQ-s) and 88.34 μg/ml (CQ-r). Overall, our results highlighted that fern-synthesized AgNP could be candidated as a new tool against chloroquine-resistant P. falciparum and different developmental instars of its primary vector An. stephensi. Further research on nanosynthesis routed by the LC/MS-identified constituents is ongoing.

Ellagitannins of the fruit rind of pomegranate (Punica granatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria.

PubMed

Dell'agli, Mario; Galli, Germana V; Bulgari, Michela; Basilico, Nicoletta; Romeo, Sergio; Bhattacharya, Deepak; Taramelli, Donatella; Bosisio, Enrica

2010-07-19

The sun-dried rind of the immature fruit of pomegranate (Punica granatum) is presently used as a herbal formulation (OMARIA, Orissa Malaria Research Indigenous Attempt) in Orissa, India, for the therapy and prophylaxis of malaria. The pathogenesis of cerebral malaria, a complication of the infection by Plasmodium falciparum, is an inflammatory cytokine-driven disease associated to an up-regulation and activity of metalloproteinase-9 and to the increase of TNF production. The in vitro anti-plasmodial activity of Punica granatum (Pg) was recently described. The aim of the present study was to explore whether the anti-malarial effect of OMARIA could also be sustained via other mechanisms among those associated to the host immune response. From the methanolic extract of the fruit rind, a fraction enriched in tannins (Pg-FET) was prepared. MMP-9 secretion and expression were evaluated in THP-1 cells stimulated with haemozoin or TNF. The assays were conducted in the presence of the Pg-FET and its chemical constituents ellagic acid and punicalagin. The effect of urolithins, the ellagitannin metabolites formed by human intestinal microflora, was also investigated. Pg-FET and its constituents inhibited the secretion of MMP-9 induced by haemozoin or TNF. The effect occurred at transcriptional level since MMP-9 mRNA levels were lower in the presence of the tested compounds. Urolithins as well inhibited MMP-9 secretion and expression. Pg-FET and pure compounds also inhibited MMP-9 promoter activity and NF-kB-driven transcription. The beneficial effect of the fruit rind of Punica granatum for the treatment of malarial disease may be attributed to the anti-parasitic activity and the inhibition of the pro-inflammatory mechanisms involved in the onset of cerebral malaria.

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

PubMed

Satish, P V V; Sunita, K

2017-09-11

The 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). The 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. Out of all the tested extracts, the methanol extract of the bark of Pongamia pinnata had shown an IC 50 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. The 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.

Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review.

PubMed

Parhizgar, Arezoo Rafiee; Tahghighi, Azar

2017-03-01

Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold.

PFMDR1 POLYMORPHISMS INFLUENCE ON IN VITRO SENSITIVITY OF THAI PLASMODIUM FALCIPARUM ISOLATES TO PRIMAQUINE, SITAMAQUINE AND TAFENOQUINE.

PubMed

Kaewpruk, Napaporn; Tan-ariya, Peerapan; Ward, Stephen A; Sitthichot, Naruemon; Suwandittakul, Nantana; Mungthin, Mathirut

2016-05-01

Primaquine (PQ), an 8-aminoquinoline, is considered a tissue schizonticide drug for radical cure in vivax and ovale malaria, with minimal impact on asexual erythrocytic stages at therapeutic concentrations. Tafenoquine (TQ), a new 8-aminoquinoline analog of PQ, is active against both malaria parasite tissue and blood stages and is being promoted as a drug candidate for antimalarial chemotherapy and chemoprophylaxis and potential transmission blocking against Plasmodium vivax and P. falciparum. This study compared in vitro sensitivity of Thai P. falciparum isolates against three 8-aminoquinolines, PQ, TQ and sitamaquine (SQ), a related 8-aminoquinoline and assessed the importance of pfmdr1 polymorphism on the in vitro response. Seventy-eight laboratory adapted Thai P. falciparum isolates were evaluated for in vitro sensitivity to the three 8-aminoquinolines using a radioisotopic assay, and pfmdr1 polymorphisms were determined using PCR-based methods. All three drugs have weak antiplasmodial activity against asexual erythrocytic stage with SQ being the most potent by almost 10 folds. Cross susceptibility was observed in all three 8-aminoquinolines. Parasites containing pfmdr1 86Y, 184Y or 1034S allele exhibit significantly higher PQ IC₅₀. TQ sensitivity was reduced in those parasites containing pfmdr1 86Y, 1034S or 1042N allele. However, there was no significant influence of pfmdr1 alleles on SQ sensitivity. The data highlight unique differences among three representative 8-aminoquinoline drugs that may be useful in understanding their potential utility in antimalarial development.

Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets

PubMed Central

Akala, Hoseah M.; Macharia, Rosaline W.; Juma, Dennis W.; Cheruiyot, Agnes C.; Andagalu, Ben; Brown, Mathew L.; El-Shemy, Hany A.; Nyanjom, Steven G.

2017-01-01

Malaria causes about half a million deaths annually, with Plasmodium falciparum being responsible for 90% of all the cases. Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for the treatment of malaria. However, most bioactive compounds fail to progress to treatments due to safety concerns. Drug repositioning offers an alternative strategy where drugs that have already been approved as safe for other diseases could be used to treat malaria. This study screened approved drugs for antimalarial activity using an in silico chemogenomics approach prior to in vitro verification. All the P. falciparum proteins sequences available in NCBI RefSeq were mined and used to perform a similarity search against DrugBank, TTD and STITCH databases to identify similar putative drug targets. Druggability indices of the potential P. falciparum drug targets were obtained from TDR targets database. Functional amino acid residues of the drug targets were determined using ConSurf server which was used to fine tune the similarity search. This study predicted 133 approved drugs that could target 34 P. falciparum proteins. A literature search done at PubMed and Google Scholar showed 105 out of the 133 drugs to have been previously tested against malaria, with most showing activity. For further validation, drug susceptibility assays using SYBR Green I method were done on a representative group of 10 predicted drugs, eight of which did show activity against P. falciparum 3D7 clone. Seven had IC50 values ranging from 1 μM to 50 μM. This study also suggests drug-target association and hence possible mechanisms of action of drugs that did show antiplasmodial activity. The study results validate the use of proteome-wide target similarity approach in identifying approved drugs with activity against P. falciparum and could be adapted for other pathogens. PMID:29088219

Tafenoquine, an Antiplasmodial 8-Aminoquinoline, Targets Leishmania Respiratory Complex III and Induces Apoptosis ▿

PubMed Central

Carvalho, Luis; Luque-Ortega, Juan Román; Manzano, José Ignacio; Castanys, Santiago; Rivas, Luis; Gamarro, Francisco

2010-01-01

Tafenoquine (TFQ), an 8-aminoquinoline analogue of primaquine, which is currently under clinical trial (phase IIb/III) for the treatment and prevention of malaria, may represent an alternative treatment for leishmaniasis. In this work, we have studied the mechanism of action of TFQ against Leishmania parasites. TFQ impaired the overall bioenergetic metabolism of Leishmania promastigotes, causing a rapid drop in intracellular ATP levels without affecting plasma membrane permeability. TFQ induced mitochondrial dysfunction through the inhibition of cytochrome c reductase (respiratory complex III) with a decrease in the oxygen consumption rate and depolarization of mitochondrial membrane potential. This was accompanied by ROS production, elevation of intracellular Ca2+ levels and concomitant nuclear DNA fragmentation. We conclude that TFQ targets Leishmania mitochondria, leading to an apoptosis-like death process. PMID:20837758

Tafenoquine, an antiplasmodial 8-aminoquinoline, targets leishmania respiratory complex III and induces apoptosis.

PubMed

Carvalho, Luis; Luque-Ortega, Juan Román; Manzano, José Ignacio; Castanys, Santiago; Rivas, Luis; Gamarro, Francisco

2010-12-01

Tafenoquine (TFQ), an 8-aminoquinoline analogue of primaquine, which is currently under clinical trial (phase IIb/III) for the treatment and prevention of malaria, may represent an alternative treatment for leishmaniasis. In this work, we have studied the mechanism of action of TFQ against Leishmania parasites. TFQ impaired the overall bioenergetic metabolism of Leishmania promastigotes, causing a rapid drop in intracellular ATP levels without affecting plasma membrane permeability. TFQ induced mitochondrial dysfunction through the inhibition of cytochrome c reductase (respiratory complex III) with a decrease in the oxygen consumption rate and depolarization of mitochondrial membrane potential. This was accompanied by ROS production, elevation of intracellular Ca(2+) levels and concomitant nuclear DNA fragmentation. We conclude that TFQ targets Leishmania mitochondria, leading to an apoptosis-like death process.

The hydroxyl functionality and a rigid proximal N are required for forming a novel non-covalent quinine-heme complex.

PubMed

Alumasa, John N; Gorka, Alexander P; Casabianca, Leah B; Comstock, Erica; de Dios, Angel C; Roepe, Paul D

2011-03-01

Quinoline antimalarial drugs bind both monomeric and dimeric forms of free heme, with distinct preferences depending on the chemical environment. Under biological conditions, chloroquine (CQ) appears to prefer to bind to μ-oxo dimeric heme, while quinine (QN) preferentially binds monomer. To further explore this important distinction, we study three newly synthesized and several commercially available QN analogues lacking various functional groups. We find that removal of the QN hydroxyl lowers heme affinity, hemozoin (Hz) inhibition efficiency, and antiplasmodial activity. Elimination of the rigid quinuclidyl ring has similar effects, but elimination of either the vinyl or methoxy group does not. Replacing the quinuclidyl N with a less rigid tertiary aliphatic N only partially restores activity. To further study these trends, we probe drug-heme interactions via NMR studies with both Fe and Zn protoporphyrin IX (FPIX, ZnPIX) for QN, dehydroxyQN (DHQN), dequinuclidylQN (DQQN), and deamino-dequinuclidylQN (DADQQN). Magnetic susceptibility measurements in the presence of FPIX demonstrate that these compounds differentially perturb FPIX monomer-dimer equilibrium. We also isolate the QN-FPIX complex formed under mild aqueous conditions and analyze it by mass spectrometry, as well as fluorescence, vibrational, and solid-state NMR spectroscopies. The data elucidate key features of QN pharmacology and allow us to propose a refined model for the preferred binding of QN to monomeric FPIX under biologically relevant conditions. With this model in hand, we also propose how QN, CQ, and amodiaquine (AQ) differ in their ability to inhibit Hz formation. Copyright © 2010 Elsevier Inc. All rights reserved.

On the molecular basis of the activity of the antimalarial drug chloroquine: EXAFS-assisted DFT evidence of a direct Fe-N bond with free heme in solution

NASA Astrophysics Data System (ADS)

Macetti, Giovanni; Rizzato, Silvia; Beghi, Fabio; Silvestrini, Lucia; Lo Presti, Leonardo

2016-02-01

4-aminoquinoline antiplasmodials interfere with the biocrystallization of the malaria pigment, a key step of the malaria parasite metabolism. It is commonly believed that these drugs set stacking π···π interactions with the Fe-protoporphyrin scaffold of the free heme, even though the details of the heme:drug recognition process remain elusive. In this work, the local coordination of Fe(III) ions in acidic solutions of hematin at room temperature was investigated by extended x-ray absorption fine structure (EXAFS) spectroscopy in the 4.0-5.5 pH range, both in the presence and in the absence of the antimalarial drug chloroquine. EXAFS results were complemented by DFT simulations in polarizable continuum media to model solvent effects. We found evidence that a complex where the drug quinoline nitrogen is coordinated with the iron center might coexist with formerly proposed adduct geometries, based on stacking interactions. Charge-assisted hydrogen bonds among lateral chains of the two molecules play a crucial role in stabilizing this complex, whose formation is favored by the presence of lipid micelles. The direct Fe-N bond could reversibly block the axial position in the Fe 1st coordination shell in free heme, acting as an inhibitor for the crystallization of the malaria pigment without permanently hampering the catalytic activity of the redox center. These findings are discussed in the light of possible implications on the engineering of drugs able to thwart the adaptability of the malaria parasite against classical aminoquinoline-based therapies.

Methylene blue inhibits lumefantrine-resistant Plasmodium berghei.

PubMed

Mwangi, Victor Irungu; Mumo, Ruth Mwende; Kiboi, Daniel Muthui; Omar, Sabah Ahmed; Ng'ang'a, Zipporah Waithera; Ozwara, Hastings Suba

2016-06-30

Chemotherapy still is the most effective way to control malaria, a major public health problem in sub-Saharan Africa. The large-scale use of the combination therapy artemether-lumefantrine for malaria treatment in Africa predisposes lumefantrine to emergence of resistance. There is need to identify drugs that can be used as substitutes to lumefantrine for use in combination therapy. Methylene blue, a synthetic anti-methemoglobinemia drug, has been shown to contain antimalarial properties, making it a candidate for drug repurposing. The present study sought to determine antiplasmodial effects of methylene blue against lumefantrine- and pyrimethamine-resistant strains of P. berghei. Activity of methylene blue was assessed using the classical four-day test on mice infected with lumefantrine-resistant and pyrimethamine-resistant P. berghei. A dose of 45 mg/kg/day was effective for testing ED90. Parasitemia and mice survival was determined. At 45 mg/kg/day, methylene blue sustained significant parasite inhibition, over 99%, for at least 6 days post-treatment against lumefantrine-resistant and pyrimethamine-resistant P. berghei (p = 0.0086 and p = 0.0191, respectively). No serious adverse effects were observed. Our results indicate that methylene blue at a concentration of 45 mg/kg/day confers over 99% inhibition against lumefantrine- and pyrimethamine-resistant P. berghei for six days. This shows the potential use methylene blue in the development of antimalarials against lumefantrine- and pyrimethamine-resistant parasites.

Evaluation of Senna singueana leaf extract as an alternative or adjuvant therapy for malaria

PubMed Central

Hiben, Mebrahtom Gebrelibanos; Sibhat, Gereziher Gebremedhin; Fanta, Biruk Sintayehu; Gebrezgi, Haile Desta; Tesema, Shewaye Belay

2015-01-01

The emergence of malarial resistance to most antimalarial drugs is the main factor driving the continued effort to identify/discover new agents for combating the disease. Moreover, the unacceptably high mortality rate in severe malaria has led to the consideration of adjuvant therapies. Senna singueana leaves are traditionally used against malaria and fever. Extracts from the leaves of this plant demonstrated in vitro and in vivo antioxidant activities, which in turn could reduce the severity of malaria. Extracts from the root bark of this plant exhibited antiplasmodial activity; however, the leaves are the more sustainable resource. Thus, S. singueana leaf was selected for in vivo evaluation as a potential alternative or adjuvant therapy for malaria. Using malaria [Plasmodium berghei ANKA, chloroquine (CQ) sensitive]-infected Swiss albino mice of both sexes, 70% ethanol extract of S. singueana leaves (alone and in combination with CQ) was tested for antimalarial activity and adjuvancy potential. The 4-day suppressive test was used to evaluate antimalarial activity. The dose of S. singueana extract administered was safe to mice and exhibited some parasite suppression effect: extract doses of 200 mg/kg/d, 400 mg/kg/d, and 800 mg/kg/d caused 34.54%, 44.52%, and 47.32% parasite suppression, respectively. Concurrent administration of the extract with CQ phosphate at varied dose levels indicated that the percentage of parasite suppression of this combination was higher than administering CQ alone, but less than the sum of the effects of the extract and CQ acting separately. In conclusion, the study indicated that 70% ethanol extract of S. singueana leaf was safe to mice and possessed some parasite suppression effect. Coadministration of the extract with CQ appeared to boost the overall antimalarial effect, indicating that the combination may have a net health benefit if used as an adjuvant therapy. PMID:26870688

Evaluation of Senna singueana leaf extract as an alternative or adjuvant therapy for malaria.

PubMed

Hiben, Mebrahtom Gebrelibanos; Sibhat, Gereziher Gebremedhin; Fanta, Biruk Sintayehu; Gebrezgi, Haile Desta; Tesema, Shewaye Belay

2016-01-01

The emergence of malarial resistance to most antimalarial drugs is the main factor driving the continued effort to identify/discover new agents for combating the disease. Moreover, the unacceptably high mortality rate in severe malaria has led to the consideration of adjuvant therapies. Senna singueana leaves are traditionally used against malaria and fever. Extracts from the leaves of this plant demonstrated in vitro and in vivo antioxidant activities, which in turn could reduce the severity of malaria. Extracts from the root bark of this plant exhibited antiplasmodial activity; however, the leaves are the more sustainable resource. Thus, S. singueana leaf was selected for in vivo evaluation as a potential alternative or adjuvant therapy for malaria. Using malaria [Plasmodium berghei ANKA, chloroquine (CQ) sensitive]-infected Swiss albino mice of both sexes, 70% ethanol extract of S. singueana leaves (alone and in combination with CQ) was tested for antimalarial activity and adjuvancy potential. The 4-day suppressive test was used to evaluate antimalarial activity. The dose of S. singueana extract administered was safe to mice and exhibited some parasite suppression effect: extract doses of 200 mg/kg/d, 400 mg/kg/d, and 800 mg/kg/d caused 34.54%, 44.52%, and 47.32% parasite suppression, respectively. Concurrent administration of the extract with CQ phosphate at varied dose levels indicated that the percentage of parasite suppression of this combination was higher than administering CQ alone, but less than the sum of the effects of the extract and CQ acting separately. In conclusion, the study indicated that 70% ethanol extract of S. singueana leaf was safe to mice and possessed some parasite suppression effect. Coadministration of the extract with CQ appeared to boost the overall antimalarial effect, indicating that the combination may have a net health benefit if used as an adjuvant therapy.

Ellagitannins of the fruit rind of pomegranate (Punica granatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria

PubMed Central

2010-01-01

Background The sun-dried rind of the immature fruit of pomegranate (Punica granatum) is presently used as a herbal formulation (OMARIA, Orissa Malaria Research Indigenous Attempt) in Orissa, India, for the therapy and prophylaxis of malaria. The pathogenesis of cerebral malaria, a complication of the infection by Plasmodium falciparum, is an inflammatory cytokine-driven disease associated to an up-regulation and activity of metalloproteinase-9 and to the increase of TNF production. The in vitro anti-plasmodial activity of Punica granatum (Pg) was recently described. The aim of the present study was to explore whether the anti-malarial effect of OMARIA could also be sustained via other mechanisms among those associated to the host immune response. Methods From the methanolic extract of the fruit rind, a fraction enriched in tannins (Pg-FET) was prepared. MMP-9 secretion and expression were evaluated in THP-1 cells stimulated with haemozoin or TNF. The assays were conducted in the presence of the Pg-FET and its chemical constituents ellagic acid and punicalagin. The effect of urolithins, the ellagitannin metabolites formed by human intestinal microflora, was also investigated. Results Pg-FET and its constituents inhibited the secretion of MMP-9 induced by haemozoin or TNF. The effect occurred at transcriptional level since MMP-9 mRNA levels were lower in the presence of the tested compounds. Urolithins as well inhibited MMP-9 secretion and expression. Pg-FET and pure compounds also inhibited MMP-9 promoter activity and NF-kB-driven transcription. Conclusions The beneficial effect of the fruit rind of Punica granatum for the treatment of malarial disease may be attributed to the anti-parasitic activity and the inhibition of the pro-inflammatory mechanisms involved in the onset of cerebral malaria. PMID:20642847

The genus Psiadia: Review of traditional uses, phytochemistry and pharmacology.

PubMed

Mahadeo, Keshika; Grondin, Isabelle; Kodja, Hippolyte; Soulange Govinden, Joyce; Jhaumeer Laulloo, Sabina; Frederich, Michel; Gauvin-Bialecki, Anne

2018-01-10

The genus Psiadia Jacq. ex. Willd. belongs to the Asteraceae family and includes more than 60 species. This genus grows in tropical and subtropical regions, being especially well represented in Madagascar and the Mascarene Islands (La Réunion, Mauritius and Rodrigues). Several Psiadia species have been used traditionally for their medicinal properties in Africa and the Mascarene Islands. Based on traditional knowledge, various phytochemical and pharmacological studies have been conducted. However there are no recent papers that provide an overview of the medicinal potential of Psiadia species. Therefore, the aim of this review is to provide a comprehensive summary of the botany, phytochemistry and pharmacology of Psiadia and to highlight the gaps in our knowledge for future research opportunities. The available information on traditional uses, phytochemistry and biological activities of the genus Psiadia was collected from scientific databases through a search using the keyword 'Psiadia' in 'Google Scholar', 'Pubmed', 'Sciencedirect', 'SpringerLink', 'Web of Science', 'Wiley' and 'Scifinder'. Additionally, published books and unpublished Ph.D. and MSc. dissertations were consulted for botanical information and chemical composition. Historically, species of the genus Psiadia have been used to treat a wide range of ailments including abdominal pains, colds, fevers, bronchitis, asthma, rheumatoid arthritis, skin infections and liver disorders among others. Phytochemical works led to the isolation of flavonoids, phenylpropanoids, coumarins and terpenoids. Furthermore, phytochemical compositions of the essential oils of some species have been evaluated. Crude extracts, essential oils and isolated molecules showed in vitro pharmacological activities, such as antimicrobial, anti-viral, anti-inflammatory, antiplasmodial and antileishmanial activities. Crude extracts of Psiadia dentata and Psiadia arguta have specifically been found to be potentially useful for inhibition of growth of Plasmodium falciparum. However, pharmacological data on this particular genus is quite limited. Further research is necessary to determine the active compounds and the underlying mechanisms. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

High-Density Peptide Arrays for Malaria Vaccine Development.

PubMed

Loeffler, Felix F; Pfeil, Johannes; Heiss, Kirsten

2016-01-01

The development of an efficacious and practicable vaccine conferring sterile immunity towards a Plasmodium infection represents a not yet achieved goal. A crucial factor for the impact of a given anti-plasmodial subunit vaccine is the identification of the most potent parasitic components required to induce protection from both infection and disease. Here, we present a method based on a novel high-density peptide array technology that allows for a flexible readout of malaria antibodies. Peptide arrays applied as a screening method can be used to identify novel immunogenic antibody epitopes under a large number of potential antigens/peptides. Ultimately, discovered antigen candidates and/or epitope sequences can be translated into vaccine prototype design. The technology can be further utilized to unravel antibody-mediated immune responses (e.g., involved in the establishment of semi-immunity) and moreover to confirm vaccine potency during the process of clinical development by verifying the induced antibody responses following vaccination.

Jozilebomines A and B, Naphthylisoquinoline Dimers from the Congolese Liana Ancistrocladus ileboensis, with Antiausterity Activities against the PANC-1 Human Pancreatic Cancer Cell Line.

PubMed

Li, Jun; Seupel, Raina; Bruhn, Torsten; Feineis, Doris; Kaiser, Marcel; Brun, Reto; Mudogo, Virima; Awale, Suresh; Bringmann, Gerhard

2017-10-27

Two new naphthylisoquinoline dimers, jozilebomines A (1a) and B (1b), were isolated from the roots of the Congolese plant Ancistrocladus ileboensis, along with the known dimer jozimine A 2 (2). These compounds are Dioncophyllaceae-type metabolites, i.e., lacking oxygen functions at C-6 and with an R-configuration at C-3 in their tetrahydroisoquinoline moieties. The dimers 1a and 1b consist of two 7,1'-coupled naphthylisoquinoline monomers linked through an unprecedented 3',6″-coupling in the binaphthalene core and not, as in 2, via the C-3-positions of the two naphthalene units. Thus, different from the C 2 -symmetric jozimine A 2 (2), the new jozilebomines are constitutionally unsymmetric. The central biaryl axis of each of the three dimers is rotationally hindered, so that 1a, 1b, and 2 possess three consecutive chiral axes. The two jozilebomines have identical constitutions and the same absolute configurations at all four stereogenic centers, but differ from each other in their axial chirality. Their structural elucidation was achieved by HRESIMS, 1D and 2D NMR, oxidative degradation, and experimental and calculated ECD data. They exhibited distinct and specific antiplasmodial activities. All dimers showed potent cytotoxicity against HeLa human cervical cancer cells and preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived conditions. Furthermore, these dimers significantly inhibited the colony formation of PANC-1 cells, even when exposed to noncytotoxic concentration for a short time. Jozilebomines A (1a) and B (1b) and jozimine A 2 (2) represent novel potential candidates for future drug development against pancreatic cancer.

Harmine blocks herpes simplex virus infection through downregulating cellular NF-κB and MAPK pathways induced by oxidative stress.

PubMed

Chen, Deyan; Su, Airong; Fu, Yuxuan; Wang, Xiaohui; Lv, Xiaowen; Xu, Wentao; Xu, Shijie; Wang, Huanru; Wu, Zhiwei

2015-11-01

Herpes simplex virus types 1 and 2 (HSV-1 and -2) are highly prevalent in many populations and therapeutic options are limited. Both viruses can establish latency by maintaining viral genomes in neurons of sensory ganglia. Primary or recurrent HSV infections may lead to deleterious outcomes: HSV-1 infection may result in corneal blindness and encephalitis and HSV-2 infection leads to herpes genitalis. While no effective vaccine is available, acyclovir is widely used for therapy, which targets and inhibits viral DNA polymerase. Although acyclovir is of low toxicity, resistant strains arise due to persistent use, mainly in immune compromised patients. In our effort to identify new HSV inhibitory molecules, harmine was found to potently inhibit HSV infection. Harmine, a beta-carbon alkaloid with an indole core structure and a pyridine ring, is widely distributed in plants. Earlier studies showed that harmine exhibited pharmacological activities such as antifungal, antimicrobial, antitumor, antiplasmodial and antioxidants. In the current study, we showed that harmine was a potent inhibitor of HSV-2 infection in vitro assays with EC50 value at around 1.47μM and CC50 value at around 337.10μM. The HSV RNA transcription, protein synthesis, and virus titers were reduced by the presence of harmine in a dose dependent manner. Further study on the mechanism of the anti-HSV activity showed that harmine blocked HSV-induced ROS production and the upregulated cytokine/chemokine expression, but our evidence showed that the inhibition of viral replication was unlikely mediated by the blocking of ROS production. We demonstrated that harmine significantly reduced HSV-2-induced NF-κB activation, as well as IκB-α degradation and p65 nuclear translocation. We found that harmine also inhibited HSV-2-mediated p38 kinase and c-Jun N-terminal kinases (JNK) phosphorylation. Copyright © 2015 Elsevier B.V. All rights reserved.

In vivo antiplasmodial and toxicological effect of crude ethanol extract of Echinops kebericho traditionally used in treatment of malaria in Ethiopia.

PubMed

Toma, Alemayehu; Deyno, Serawit; Fikru, Abrham; Eyado, Amalework; Beale, Andrew

2015-05-10

Medicinal plants have contributed significantly to current malaria treatment. Emergence of resistance to currently available drugs has necessitated the search for new plant-based anti-malarial agents and several plant-based, pharmacologically active anti-malarial compounds have been isolated. This study was conducted to validate the traditional usage of Echinops kebericho for treating malaria in the traditional health care system of Ethiopia. The roots of E. kebericho were collected from Masha Woreda, Sheka Zone. After collection, the plant materials were identified by a taxonomist, dried under shade and crushed to powder for extraction. The powdered roots were extracted by maceration using 70 % ethanol. Acute toxicity study of the crude extract was carried out in Swiss albino mice. The in vivo anti-malarial activity of plant extract (200, 350 and 500 mg/kg) of E. kebericho roots against a chloroquine (CQ) sensitive strain of Plasmodium berghei strain ANKA was assessed using the four-day suppressive test procedure. Parameters such as parasitaemia, packed cell volume, body weight and survival time were then determined using standard tests. Oral administration of the ethanol extract showed significant (P<0.001) parasitaemia suppression at dose levels of 350 and 500 mg/kg in dose-related manner compared with the negative control. Five hundred mg/kg showed the highest (57.29±1.76 %) parasitaemia suppression. The survival times of P. berghei-infected mice were also increased in a dose-dependent manner but the test material did not prevent weight loss associated with increased parasitaemia. The result also showed the plant material prevented the loss in packed cell volume associated with increased parasitaemia. Its oral LD50 was found to be greater than 5,000 mg/kg, indicating its wider safety margin in mice. The result revealed the ethanol extract of E. kebericho roots has anti-malarial activity against P. berghei in an animal model and lends support to the use of the plant to combat malaria in Ethiopian folk medicine. Further work is necessary to isolate, identify and characterize the active principles from the plant material.

Development and decline of antiplasmodial indirect fluorescent antibodies in mice infected with Plasmodium berghei (NK65) and treated with drugs

PubMed Central

Waki, Seiji; Suzuki, Mamoru

1974-01-01

Malaria parasites in mice present a simplified rodent model for the immunological study of malaria. Experiments have been performed to determine the pattern and persistence of malaria antibody as detected by the indirect fluorescent antibody (IFA) test utilizing specific antimouse IgM and IgG conjugates. The antibody levels in mice inoculated with Plasmodium berghei and treated with antimalarial drugs were traced after complete elimination of the parasites from the host. Within 1-2 weeks after inoculation, both specific IgM and IgG reached peak levels, which thereafter declined rapidly. The results suggest that a high IFA titre may be taken as an indication of recent parasitaemia when the parasites are absent from the host. The protective role of the specific immunoglobulin was not found in the cured animals at the time when the animals showed a high IFA titer. It seems that the detected IFA may not reflect protective immunity against reinfection with malaria parasites. PMID:4617640

2-Hexadecynoic acid inhibits plasmodial FAS-II enzymes and arrests erythrocytic and liver stage Plasmodium infections.

PubMed

Tasdemir, Deniz; Sanabria, David; Lauinger, Ina L; Tarun, Alice; Herman, Rob; Perozzo, Remo; Zloh, Mire; Kappe, Stefan H; Brun, Reto; Carballeira, Néstor M

2010-11-01

Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodium falciparum and liver stages of Plasmodium yoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC(50) value 6.6 μg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC(50) value 2-HDA 15.3 μg/ml, control drug atovaquone 2.5 ng/ml) and immunofluorescence analysis (IC(50) 2-HDA 4.88 μg/ml, control drug atovaquone 0.37 ng/ml). 2-HDA showed the best inhibitory activity against the PfFAS-II enzymes PfFabI and PfFabZ with IC(50) values of 0.38 and 0.58 μg/ml (IC(50) control drugs 14 and 30 ng/ml), respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosoma brucei rhodesiense (IC(50) values 3.7-31.7 μg/ml), Trypanosoma cruzi (only 2-HDA, IC(50) 20.2 μg/ml), and Leishmania donovani (IC(50) values 4.1-13.4 μg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature, and calculated pharmacokinetic properties suggests that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes. Copyright © 2010 Elsevier Ltd. All rights reserved.

2-Hexadecynoic Acid Inhibits Plasmodial FAS-II Enzymes and Arrest Erythrocytic and Liver Stage Plasmodium Infections

PubMed Central

Tasdemir, Deniz; Sanabria, David; Lauinger, Ina L.; Tarun, Alice; Herman, Rob; Perozzo, Remo; Zloh, Mire; Kappe, Stefan H.; Brun, Reto; Carballeira, Néstor M.

2010-01-01

Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodium falciparum and liver stages of P. yoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC50 value 6.6. μg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC50 value 2-HDA 15.3 μg/ml, control drug atovaquone 2.5 ng/ml) and immunofluorescense analysis (IC50 2-HDA 4.88 μg/ml, control drug atovaquone 0.37 ng/ml). 2-HDA showed the best inhibitory against the PfFAS-II enzymes PfFabI and PfFabZ with IC50 values of 0.38 and 0.58 μg/ml (IC50 control drugs 14 and 30 ng/ml) respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosoma brucei rhodesiense (IC50 values 3.7–31.7 μg/ml), Trypanosoma cruzi (only 2-HDA, IC50 20.2 μg/ml), and Leishmania donovani (IC50 values 4.1–13.4 μg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature and calculated pharmacokinetic properties suggest that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes. PMID:20855214

Domino syntheses of bioactive tetronic and tetramic acids.

PubMed

Schobert, Rainer

2007-01-01

Natural products containing tetronic acid or tetramic acid moieties continue to attract the interest of chemists, biologists, and physicians due to their challenging structures and to the wide range of biological activities they display. This review portrays the structural varieties of tetronic and tetramic acids and the spectrum of possible therapeutically relevant effects in man for exemplary derivatives. Their biosynthetic origin from alpha-amino and alpha-hydroxy acids is briefly discussed as is the relationship between their structures and their modes of interaction with biochemical effectors such as metal cations or enzymes. A short overview of laboratory syntheses of the heterocyclic core structures of tetramic and tetronic acids is provided with an emphasis on those emulating the biosynthesis. A synthesis from the alpha-amino or alpha-hydroxy esters and the cumulated phosphorus ylide Ph(3)PCCO based upon a domino addition-intra-Wittig alkenation sequence is presented with applications to the preparation of the antibiotics reutericyclin and tenuazonic acid, the cytotoxic melophlin B, and the enzyme inhibitor RK-682. Procedural advantages of immobilizing either starting component by attaching it to a resin and its exploitation in the parallel synthesis of libraries of potential drug candidates are described. The basic domino reaction can even be extended by further C-C bond forming steps when starting from suitable alpha-hydroxy or alpha-amino allyl esters. Depending on the chosen reaction conditions, bioactive intermediates of formally three to seven step long cascades can be obtained. Among them, herbicidal 3-alkyltetronic acids and lactone endoperoxides with antiplasmodial activity exceeding that of the natural antimalarial lead artemisinin. Hence, this domino reaction gives access to diversely functionalized derivatives of tetronic and tetramic acids. As it can also be ported to solid phase, it is ideally suited for parallel and combinatorial processing. Future developments might include running such domino sequences in continuous mode in arrays of "labs on microchips".

Domino syntheses of bioactive tetronic and tetramic acids

NASA Astrophysics Data System (ADS)

Schobert, Rainer

2007-01-01

Natural products containing tetronic acid or tetramic acid moieties continue to attract the interest of chemists, biologists, and physicians due to their challenging structures and to the wide range of biological activities they display. This review portrays the structural varieties of tetronic and tetramic acids and the spectrum of possible therapeutically relevant effects in man for exemplary derivatives. Their biosynthetic origin from α-amino and α-hydroxy acids is briefly discussed as is the relationship between their structures and their modes of interaction with biochemical effectors such as metal cations or enzymes. A short overview of laboratory syntheses of the heterocyclic core structures of tetramic and tetronic acids is provided with an emphasis on those emulating the biosynthesis. A synthesis from the α-amino or α-hydroxy esters and the cumulated phosphorus ylide Ph3PCCO based upon a domino addition-intra-Wittig alkenation sequence is presented with applications to the preparation of the antibiotics reutericyclin and tenuazonic acid, the cytotoxic melophlin B, and the enzyme inhibitor RK-682. Procedural advantages of immobilizing either starting component by attaching it to a resin and its exploitation in the parallel synthesis of libraries of potential drug candidates are described. The basic domino reaction can even be extended by further C-C bond forming steps when starting from suitable α-hydroxy or α-amino allyl esters. Depending on the chosen reaction conditions, bioactive intermediates of formally three to seven step long cascades can be obtained. Among them, herbicidal 3-alkyltetronic acids and lactone endoperoxides with antiplasmodial activity exceeding that of the natural antimalarial lead artemisinin. Hence, this domino reaction gives access to diversely functionalized derivatives of tetronic and tetramic acids. As it can also be ported to solid phase, it is ideally suited for parallel and combinatorial processing. Future developments might include running such domino sequences in continuous mode in arrays of “labs on microchips”.

Fighting malaria with engineered symbiotic bacteria from vector mosquitoes.

PubMed

Wang, Sibao; Ghosh, Anil K; Bongio, Nicholas; Stebbings, Kevin A; Lampe, David J; Jacobs-Lorena, Marcelo

2012-07-31

The most vulnerable stages of Plasmodium development occur in the lumen of the mosquito midgut, a compartment shared with symbiotic bacteria. Here, we describe a strategy that uses symbiotic bacteria to deliver antimalaria effector molecules to the midgut lumen, thus rendering host mosquitoes refractory to malaria infection. The Escherichia coli hemolysin A secretion system was used to promote the secretion of a variety of anti-Plasmodium effector proteins by Pantoea agglomerans, a common mosquito symbiotic bacterium. These engineered P. agglomerans strains inhibited development of the human malaria parasite Plasmodium falciparum and rodent malaria parasite Plasmodium berghei by up to 98%. Significantly, the proportion of mosquitoes carrying parasites (prevalence) decreased by up to 84% for two of the effector molecules, scorpine, a potent antiplasmodial peptide and (EPIP)(4), four copies of Plasmodium enolase-plasminogen interaction peptide that prevents plasminogen binding to the ookinete surface. We demonstrate the use of an engineered symbiotic bacterium to interfere with the development of P. falciparum in the mosquito. These findings provide the foundation for the use of genetically modified symbiotic bacteria as a powerful tool to combat malaria.

Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins

PubMed Central

Hanson, Kirsten K.; Ressurreição, Ana S.; Buchholz, Kathrin; Prudêncio, Miguel; Herman-Ornelas, Jonathan D.; Rebelo, Maria; Beatty, Wandy L.; Wirth, Dyann F.; Hänscheid, Thomas; Moreira, Rui; Marti, Matthias; Mota, Maria M.

2013-01-01

Residence within a customized vacuole is a highly successful strategy used by diverse intracellular microorganisms. The parasitophorous vacuole membrane (PVM) is the critical interface between Plasmodium parasites and their possibly hostile, yet ultimately sustaining, host cell environment. We show that torins, developed as ATP-competitive mammalian target of rapamycin (mTOR) kinase inhibitors, are fast-acting antiplasmodial compounds that unexpectedly target the parasite directly, blocking the dynamic trafficking of the Plasmodium proteins exported protein 1 (EXP1) and upregulated in sporozoites 4 (UIS4) to the liver stage PVM and leading to efficient parasite elimination by the hepatocyte. Torin2 has single-digit, or lower, nanomolar potency in both liver and blood stages of infection in vitro and is likewise effective against both stages in vivo, with a single oral dose sufficient to clear liver stage infection. Parasite elimination and perturbed trafficking of liver stage PVM-resident proteins are both specific aspects of torin-mediated Plasmodium liver stage inhibition, indicating that torins have a distinct mode of action compared with currently used antimalarials. PMID:23836641

Brine shrimp toxicity and antimalarial activity of some plants traditionally used in treatment of malaria in Msambweni district of Kenya.

PubMed

Nguta, J M; Mbaria, J M

2013-07-30

In Kenya, most people especially in rural areas use traditional medicine and medicinal plants to treat many diseases including malaria. Malaria is of national concern in Kenya, in view of development of resistant strains of Plasmodium falciparum to drugs especially chloroquine, which had been effective and affordable. There is need for alternative and affordable therapy. Many antimalarial drugs have been derived from medicinal plants and this is evident from the reported antiplasmodial activity. The present study reports on the in vivo antimalarial activity and brine shrimp lethality of five medicinal plants traditionally used to treat malaria in Msambweni district, Kenya. A total of five aqueous crude extracts from different plant parts used in traditional medicine for the treatment of malaria were evaluated for their in vivo antimalarial activity using Plasmodium berghei infected Swiss mice and for their acute toxicity using Brine shrimp lethality test. The screened crude plant extracts suppressed parasitaemia as follows: Azadirachta indica (L) Burm. (Meliaceae), 3.1%; Dichrostachys cinerea (L) Wight et Arn (Mimosaceae), 6.3%; Tamarindus indica L. (Caesalpiniaceae), 25.1%; Acacia seyal Del. (Mimosaceae) 27.8% and Grewia trichocarpa Hochst ex A.Rich (Tiliaceae) 35.8%. In terms of toxicity, A.indica root bark extract had an LC50 of 285.8 µg/ml and was considered moderately toxic. T.indica stem bark extract and G.trichocarpa root extract had an LC50 of 516.4 and 545.8 µg/ml respectively and were considered to be weakly toxic while A.seyal and D.cinerea root extracts had a LC50>1000 µg/ml and were therefore considered to be non toxic. The results indicate that the aqueous extracts of the tested plants when used alone as monotherapy had antimalarial activity which was significantly different from that of chloroquine (P≤0.05). The results also suggest that the anecdotal efficacy of the above plants reported by the study community is related to synergism of phytoconstituents since the assayed plant parts are used in combination with others to treat malaria. It is also evident that none of the screened plant extracts is toxic to the arthropod invertebrate, Artemia salina L. (Artemiidae) larvae, justifying the continued use of the plant parts to treat malaria. A.seyal, G.trichocarpa and T.indica have not been reported before for in vivo antimalarial activity and brine shrimp lethality. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

The Measurement of Subjective Value and Its Relation to Contingent Valuation and Environmental Public Goods

PubMed Central

Khaw, Mel W.; Grab, Denise A.; Livermore, Michael A.; Vossler, Christian A.; Glimcher, Paul W.

2015-01-01

Environmental public goods—including national parks, clean air/water, and ecosystem services—provide substantial benefits on a global scale. These goods have unique characteristics in that they are typically “nonmarket” goods, with values from both use and passive use that accrue to a large number of individuals both in current and future generations. In this study, we test the hypothesis that neural signals in areas correlated with subjective valuations for essentially all other previously studied categories of goods (ventromedial prefrontal cortex and ventral striatum) also correlate with environmental valuations. We use contingent valuation (CV) as our behavioral tool for measuring valuations of environmental public goods. CV is a standard stated preference approach that presents survey respondents with information on an issue and asks questions that help policymakers determine how much citizens are willing to pay for a public good or policy. We scanned human subjects while they viewed environmental proposals, along with three other classes of goods. The presentation of all four classes of goods yielded robust and similar patterns of temporally synchronized brain activation within attentional networks. The activations associated with the traditional classes of goods replicate previous correlations between neural activity in valuation areas and behavioral preferences. In contrast, CV-elicited values for environmental proposals did not correlate with brain activity at either the individual or population level. For a sub-population of participants, CV-elicited values were correlated with activity within the dorsomedial prefrontal cortex, a region associated with cognitive control and shifting decision strategies. The results show that neural activity associated with the subjective valuation of environmental proposals differs profoundly from the neural activity associated with previously examined goods and preference measures. PMID:26221734

Green-synthesized CdS nano-pesticides: Toxicity on young instars of malaria vectors and impact on enzymatic activities of the non-target mud crab Scylla serrata.

PubMed

Sujitha, Vasu; Murugan, Kadarkarai; Dinesh, Devakumar; Pandiyan, Amuthvalli; Aruliah, Rajasekar; Hwang, Jiang-Shiou; Kalimuthu, Kandasamy; Panneerselvam, Chellasamy; Higuchi, Akon; Aziz, Al Thabiani; Kumar, Suresh; Alarfaj, Abdullah A; Vaseeharan, Baskaralingam; Canale, Angelo; Benelli, Giovanni

2017-07-01

Currently, nano-formulated mosquito larvicides have been widely proposed to control young instars of malaria vector populations. However, the fate of nanoparticles in the aquatic environment is scarcely known, with special reference to the impact of nanoparticles on enzymatic activity of non-target aquatic invertebrates. In this study, we synthesized CdS nanoparticles using a green protocol relying on the cheap extract of Valoniopsis pachynema algae. CdS nanoparticles showed high toxicity on young instars of the malaria vectors Anopheles stephensi and A. sundaicus. The antimalarial activity of the nano-synthesized product against chloroquine-resistant (CQ-r) Plasmodium falciparum parasites was investigated. From a non-target perspective, we focused on the impact of this novel nano-pesticide on antioxidant enzymes acetylcholinesterase (AChE) and glutathione S-transferase (GST) activities of the mud crab Scylla serrata. The characterization of nanomaterials was carried out by UV-vis and FTIR spectroscopy, as well as SEM and XRD analyses. In mosquitocidal assays, LC 50 of V. pachynema-synthesized CdS nanoparticles on A. stephensi ranged from 16.856 (larva I), to 30.301μg/ml (pupa), while for An. sundaicus they ranged from 13.584 to 22.496μg/ml. The antiplasmodial activity of V. pachynema extract and CdS nanoparticles was evaluated against CQ-r and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. IC 50 of V. pachynema extract was 58.1μg/ml (CQ-s) and 71.46μg/ml (CQ-r), while nano-CdS IC 50 was 76.14μg/ml (CQ-s) and 89.21μg/ml (CQ-r). In enzymatic assays, S. serrata crabs were exposed to sub-lethal concentrations, i.e. 4, 6 and 8μg/ml of CdS nanoparticles, assessing changes in GST and AChE activity after 16days. We observed significantly higher activity of GST, if compared to the control, during the whole experiment period. In addition, a single treatment with CdS nanoparticles led to a significant decrease in AChE activity over time. The toxicity of CdS nanoparticles and Cd ions in aqueous solution was also assessed in mud crabs, showing higher toxicity of aqueous Cd ions if compared to nano-CdS. Overall, our results underlined the efficacy of green-synthesized CdS nanoparticles in malaria vector control, outlining also significant impacts on the enzymatic activity of non-target aquatic organisms, with special reference to mud crabs. Copyright © 2017 Elsevier B.V. All rights reserved.

75 FR 60772 - Agency Information Collection Activities: Transportation Entry and Manifest of Goods Subject to...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-01

... Activities: Transportation Entry and Manifest of Goods Subject to CBP Inspection and Permit AGENCY: U.S... the Paperwork Reduction Act: Transportation Entry and Manifest of Goods Subject to CBP Inspection and... techniques or other forms of information. Title: Transportation Entry and Manifest of Goods Subject to CBP...

Literary Reading Activities of Good and Weak Students: A Think Aloud Study

ERIC Educational Resources Information Center

Janssen, Tanja; Braaksma, Martine; Rijlaarsdam, Gert

2006-01-01

In this study we examined how good and weak students of literature interact with short literary stories. We focused on differences in the use of cognitive and affective reading activities, and in the extent to which good and weak students adapt their activities to (parts of) the story they are reading. 19 Dutch tenth-grade students from 8 classes…

29 CFR 779.109 - Amount of activities which constitute engaging in commerce or in the production of goods for...

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 3 2012-07-01 2012-07-01 false Amount of activities which constitute engaging in commerce or in the production of goods for commerce. 779.109 Section 779.109 Labor Regulations Relating to... Engaged in Commerce Or in the Production of Goods for Commerce § 779.109 Amount of activities which...

29 CFR 779.109 - Amount of activities which constitute engaging in commerce or in the production of goods for...

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Amount of activities which constitute engaging in commerce or in the production of goods for commerce. 779.109 Section 779.109 Labor Regulations Relating to... Engaged in Commerce Or in the Production of Goods for Commerce § 779.109 Amount of activities which...

29 CFR 779.109 - Amount of activities which constitute engaging in commerce or in the production of goods for...

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 3 2014-07-01 2014-07-01 false Amount of activities which constitute engaging in commerce or in the production of goods for commerce. 779.109 Section 779.109 Labor Regulations Relating to... Engaged in Commerce Or in the Production of Goods for Commerce § 779.109 Amount of activities which...

29 CFR 779.109 - Amount of activities which constitute engaging in commerce or in the production of goods for...

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 3 2011-07-01 2011-07-01 false Amount of activities which constitute engaging in commerce or in the production of goods for commerce. 779.109 Section 779.109 Labor Regulations Relating to... Engaged in Commerce Or in the Production of Goods for Commerce § 779.109 Amount of activities which...

29 CFR 779.109 - Amount of activities which constitute engaging in commerce or in the production of goods for...

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 3 2013-07-01 2013-07-01 false Amount of activities which constitute engaging in commerce or in the production of goods for commerce. 779.109 Section 779.109 Labor Regulations Relating to... Engaged in Commerce Or in the Production of Goods for Commerce § 779.109 Amount of activities which...

Institutional and matrix support and its relationship with primary healthcare

PubMed Central

dos Santos, Alaneir de Fátima; Machado, Antônio Thomaz Gonzaga da Matta; dos Reis, Clarice Magalhães Rodrigues; Abreu, Daisy Maria Xavier; de Araújo, Lucas Henrique Lobato; Rodrigues, Simone Cristina; de Lima, Ângela Maria de Lourdes Dayrell; Jorge, Alzira de Oliveira; Fonseca, Délcio

2015-01-01

OBJECTIVE To analyze whether the level of institutional and matrix support is associated with better certification of primary healthcare teams. METHODS In this cross-sectional study, we evaluated two kinds of primary healthcare support – 14,489 teams received institutional support and 14,306 teams received matrix support. Logistic regression models were applied. In the institutional support model, the independent variable was “level of support” (as calculated by the sum of supporting activities for both modalities). In the matrix support model, in turn, the independent variables were the supporting activities. The multivariate analysis has considered variables with p < 0.20. The model was adjusted by the Hosmer-Lemeshow test. RESULTS The teams had institutional and matrix supporting activities (84.0% and 85.0%), respectively, with 55.0% of them performing between six and eight activities. For the institutional support, we have observed 1.96 and 3.77 chances for teams who had medium and high levels of support to have very good or good certification, respectively. For the matrix support, the chances of their having very good or good certification were 1.79 and 3.29, respectively. Regarding to the association between institutional support activities and the certification, the very good or good certification was positively associated with self-assessment (OR = 1.95), permanent education (OR = 1.43), shared evaluation (OR = 1.40), and supervision and evaluation of indicators (OR = 1.37). In regards to the matrix support, the very good or good certification was positively associated with permanent education (OR = 1.50), interventions in the territory (OR = 1.30), and discussion in the work processes (OR = 1.23). CONCLUSIONS In Brazil, supporting activities are being incorporated in primary healthcare, and there is an association between the level of support, both matrix and institutional, and the certification result. PMID:26274872

Good Concrete Activity Is Good Mental Activity

ERIC Educational Resources Information Center

McDonough, Andrea

2016-01-01

Early years mathematics classrooms can be colourful, exciting, and challenging places of learning. Andrea McDonough and fellow teachers have noticed that some students make good decisions about using materials to assist their problem solving, but this is not always the case. These experiences lead her to ask the following questions: (1) Are…

78 FR 76152 - Agency Information Collection Activities: Transportation Entry and Manifest of Goods Subject to...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-16

... Activities: Transportation Entry and Manifest of Goods Subject to CBP Inspection and Permit AGENCY: U.S... the Paperwork Reduction Act: Transportation Entry and Manifest of Goods Subject to CBP Inspection and..., mechanical, or other technological techniques or other forms of information. Title: Transportation Entry and...

Structural features, kinetics and SAR study of radical scavenging and antioxidant activities of phenolic and anilinic compounds

PubMed Central

2013-01-01

Background Phenolic compounds are widely distributed in plant kingdom and constitute one of the most important classes of natural and synthetic antioxidants. In the present study fifty one natural and synthetic structurally variant phenolic, enolic and anilinic compounds were examined as antioxidants and radical scavengers against DPPH, hydroxyl and peroxyl radicals. The structural diversity of the used phenolic compounds includes monophenols with substituents frequently present in natural phenols e.g. alkyl, alkoxy, ester and carboxyl groups, besides many other electron donating and withdrawing groups, in addition to polyphenols with 1–3 hydroxyl groups and aminophenols. Some common groups e.g. alkyl, carboxyl, amino and second OH groups were incorporated in ortho, meta and para positions. Results SAR study indicates that the most important structural feature of phenolic compounds required to possess good antiradical and antioxidant activities is the presence of a second hydroxyl or an amino group in o- or p-position because of their strong electron donating effect in these positions and the formation of a stable quinone-like products upon two hydrogen-atom transfer process; otherwise, the presence of a number of alkoxy (in o or p-position) and /or alkyl groups (in o, m or p-position) should be present to stabilize the resulted phenoxyl radical and reach good activity. Anilines showed also similar structural feature requirements as phenols to achieve good activities, except o-diamines which gave low activity because of the high energy of the resulted 1,2-dimine product upon the 2H-transfer process. Enols with ene-1,2-diol structure undergo the same process and give good activity. Good correlations were obtained between DPPH inhibition and inhibition of both OH and peroxyl radicals. In addition, good correlations were obtained between DPPH inhibition and antioxidant activities in sunflower oil and liver homogenate systems. Conclusions In conclusion, the structures of good anti radical and antioxidant phenols and anilines are defined. The obtained good correlations imply that measuring anti DPPH activity can be used as a simple predictive test for the anti hydroxyl and peroxyl radical, and antioxidant activities. Kinetic measurements showed that strong antioxidants with high activity have also high reaction rates indicating that factors stabilizing the phenoxyl radicals lower also the activation energy of the hydrogen transfer process. PMID:23497653

Brain Activation during Sentence Comprehension among Good and Poor Readers

PubMed Central

Keller, Timothy A.; Cherkassky, Vladimir L.; Lee, Donghoon; Hoeft, Fumiko; Whitfield-Gabrieli, Susan; Gabrieli, John D. E.; Just, Marcel Adam

2008-01-01

This study sought to increase current understanding of the neuro-psychological basis of poor reading ability by using fMRI to examine brain activation during a visual sentence comprehension task among good and poor readers in the third (n = 32) and fifth (n = 35) grades. Reading ability, age, and the combination of both factors made unique contributions to cortical activation. The main finding was of parietotemporal underactivation (less activation than controls) among poor readers at the 2 grade levels. A positive linear relationship (spanning both the poor and good readers) was found between reading ability and activation in the left posterior middle temporal and postcentral gyri and in the right inferior parietal lobule such that activation increased with reading ability. Different developmental trajectories characterized good and poor readers in the left angular gyrus: activation increased with age among good readers, a change that failed to occur among poor readers. The parietotemporal cortex is discussed in terms of its role in reading acquisition, with the left angular gyrus playing a key role. It is proposed that the functioning of the cortical network underlying reading is dependent on a combination of interacting factors, including physiological maturation, neural integrity, skill level, and the nature of the task. PMID:17317678

GOODS Far Infrared Imaging with Herschel

NASA Astrophysics Data System (ADS)

Frayer, David T.; Elbaz, D.; Dickinson, M.; GOODS-Herschel Team

2010-01-01

Most of the stars in galaxies formed at high redshift in dusty environments, where their energy was absorbed and re-radiated at infrared wavelengths. Similarly, much of the growth of nuclear black holes in active galactic nuclei (AGN) was also obscured from direct view at UV/optical and X-ray wavelengths. The Great Observatories Origins Deep Survey Herschel (GOODS-H) open time key program will obtain the deepest far-infrared view of the distant universe, mapping the history of galaxy growth and AGN activity over a broad swath of cosmic time. GOODS-H will image the GOODS-North field with the PACS and SPIRE instruments at 100 to 500 microns, matching the deep survey of GOODS-South in the guaranteed time key program. GOODS-H will also observe an ultradeep sub-field within GOODS-South with PACS, reaching the deepest flux limits planned for Herschel (0.6 mJy at 100 microns with S/N=5). GOODS-H data will detect thousands of luminous and ultraluminous infrared galaxies out to z=4 or beyond, measuring their far-infrared luminosities and spectral energy distributions, and providing the best constraints on star formation rates and AGN activity during this key epoch of galaxy and black hole growth in the young universe.

Exercise and Cystic Fibrosis (CF)

MedlinePlus

... all children to develop good exercise habits and attitudes. This starts early and with the family. When ... active playtime on most days helps grow good attitudes toward activity in children less than 4 years ...

The Elderly Perceived Meanings and Values of Virtual Reality Leisure Activities: A Means-End Chain Approach.

PubMed

Lin, Cheng-Shih; Jeng, Mei-Yuan; Yeh, Tsu-Ming

2018-04-03

This study uses means-end chain (MEC) techniques to examine the awareness, decision-making procedure, and personal values of the elderly with regard to virtual reality leisure activities. The results of the study show that elderly respondents value virtual reality leisure activities that are fun, safe, and easy. In terms of outcome benefits, elderly respondents value feeling physically and mentally healthy, firsthand experience, and satisfied curiosity. In value terms, elderly respondents hope that their chosen virtual reality leisure activities improve not only their relationships with others, but also their enjoyment, quality of life, and sense of belonging. The results show that, while consumers with different awarenesses of virtual reality leisure activities have different decision-making processes, they share creating "good memories" as the terminal value with the most significant effect. This presents a potential opportunity to promote virtual reality leisure activities. Relevant bodies or enterprises can seek to create good memories in consumers by developing activities that are safe and fun, promote good health, and provide good service, thereby attracting the interest of elderly consumers.

The Elderly Perceived Meanings and Values of Virtual Reality Leisure Activities: A Means-End Chain Approach

PubMed Central

Lin, Cheng-Shih; Jeng, Mei-Yuan

2018-01-01

This study uses means-end chain (MEC) techniques to examine the awareness, decision-making procedure, and personal values of the elderly with regard to virtual reality leisure activities. The results of the study show that elderly respondents value virtual reality leisure activities that are fun, safe, and easy. In terms of outcome benefits, elderly respondents value feeling physically and mentally healthy, firsthand experience, and satisfied curiosity. In value terms, elderly respondents hope that their chosen virtual reality leisure activities improve not only their relationships with others, but also their enjoyment, quality of life, and sense of belonging. The results show that, while consumers with different awarenesses of virtual reality leisure activities have different decision-making processes, they share creating “good memories” as the terminal value with the most significant effect. This presents a potential opportunity to promote virtual reality leisure activities. Relevant bodies or enterprises can seek to create good memories in consumers by developing activities that are safe and fun, promote good health, and provide good service, thereby attracting the interest of elderly consumers. PMID:29614012

Nursing home residents' self-perceived resources for good sleep.

PubMed

Herrmann, Wolfram J; Flick, Uwe

2011-12-01

To explore the nursing home residents' self-perceived resources for good sleep. A qualitative research design. Episodic interviews were conducted, and analysis was done using thematic coding. Five German nursing homes from different providers. Thirty nursing home residents who were at least 64 years old and oriented to place and person. The nursing home residents' self-perceived resources for good sleep can be classified into three general patterns: calmness, daily activity, and environmental factors. The residents see calmness as a psychological state and a prerequisite for good sleep. Rumination was reported as the main reason for disruption of calmness. Daily activity is also seen by residents to foster sleep, but most residents do not know how to be physically active. Environmental factors such as fresh air, silence, or the type of bed contribute individually to good sleep; however, nursing home residents usually lack strategies to foster these resources by themselves. The nursing home residents' self-perceived resources for good sleep--calmness, daily activity, and environmental factors--can be starting points for non-pharmacological treatment of sleep disorders. The residents' primary care physicians should explore these individual resources during consultation and attempt to foster them.

Seaweed-synthesized silver nanoparticles: an eco-friendly tool in the fight against Plasmodium falciparum and its vector Anopheles stephensi?

PubMed

Murugan, Kadarkarai; Samidoss, Christina Mary; Panneerselvam, Chellasamy; Higuchi, Akon; Roni, Mathath; Suresh, Udaiyan; Chandramohan, Balamurugan; Subramaniam, Jayapal; Madhiyazhagan, Pari; Dinesh, Devakumar; Rajaganesh, Rajapandian; Alarfaj, Abdullah A; Nicoletti, Marcello; Kumar, Suresh; Wei, Hui; Canale, Angelo; Mehlhorn, Heinz; Benelli, Giovanni

2015-11-01

Malaria, the most widespread mosquito-borne disease, affects 350-500 million people each year. Eco-friendly control tools against malaria vectors are urgently needed. This research proposed a novel method of plant-mediated synthesis of silver nanoparticles (AgNP) using a cheap seaweed extract of Ulva lactuca, acting as a reducing and capping agent. AgNP were characterized by UV-vis spectrophotometry, Fourier transform infrared (FTIR) spectroscopy, energy-dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM), and X-ray diffraction (XRD). The U. lactuca extract and the green-synthesized AgNP were tested against larvae and pupae of the malaria vector Anopheles stephensi. In mosquitocidal assays, LC50 values of U. lactuca extract against A. stephensi larvae and pupae were 18.365 ppm (I instar), 23.948 ppm (II), 29.701 ppm (III), 37.517 ppm (IV), and 43.012 ppm (pupae). LC50 values of AgNP against A. stephensi were 2.111 ppm (I), 3.090 ppm (II), 4.629 ppm (III), 5.261 ppm (IV), and 6.860 ppm (pupae). Smoke toxicity experiments conducted against mosquito adults showed that U. lactuca coils evoked mortality rates comparable to the permethrin-based positive control (66, 51, and 41%, respectively). Furthermore, the antiplasmodial activity of U. lactuca extract and U. lactuca-synthesized AgNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. Fifty percent inhibitory concentration (IC50) values of U. lactuca were 57.26 μg/ml (CQ-s) and 66.36 μg/ml (CQ-r); U. lactuca-synthesized AgNP IC50 values were 76.33 μg/ml (CQ-s) and 79.13 μg/ml (CQ-r). Overall, our results highlighted out that U. lactuca-synthesized AgNP may be employed to develop newer and safer agents for malaria control.

Dried-leaf Artemisia annua: A practical malaria therapeutic for developing countries?

PubMed Central

Weathers, Pamela J; Towler, Melissa; Hassanali, Ahmed; Lutgen, Pierre; Engeu, Patrick Ogwang

2015-01-01

Artemisinin from the plant Artemisia annua (A. annua) L, and used as artemisinin combination therapy (ACT), is the current best therapeutic for treating malaria, a disease that hits children and adults especially in developing countries. Traditionally, A. annua was used by the Chinese as a tea to treat “fever”. More recently, investigators have shown that tea infusions and oral consumption of the dried leaves of the plant have prophylactic and therapeutic efficacy. The presence of a complex matrix of chemicals within the leaves seems to enhance both the bioavailability and efficacy of artemisinin. Although about 1000-fold less potent than artemisinin in their antiplasmodial activity, these plant chemicals are mainly small molecules that include other artemisinic compounds, terpenes (mainly mono and sesqui), flavonoids, and polyphenolic acids. In addition, polysaccharide constituents of A. annua may enhance bioavailability of artemisinin. Rodent pharmacokinetics showed longer T1/2 and Tmax and greater Cmax and AUC in Plasmodium chabaudi-infected mice treated with A. annua dried leaves than in healthy mice. Pharmacokinetics of deoxyartemisinin, a liver metabolite of artemisinin, was more inhibited in infected than in healthy mice. In healthy mice, artemisinin serum levels were > 40-fold greater in dried leaf fed mice than those fed with pure artemisinin. Human trial data showed that when delivered as dried leaves, 40-fold less artemisinin was required to obtain a therapeutic response compared to pure artemisinin. ACTs are still unaffordable for many malaria patients, and cost estimates for A. annua dried leaf tablet production are orders of magnitude less than for ACT, despite improvements in the production capacity. Considering that for > 2000 years this plant was used in traditional Chinese medicine for treatment of fever with no apparent appearance of artemisinin drug resistance, the evidence argues for inclusion of affordable A. annua dried leaf tablets into the arsenal of drugs to combat malaria and other artemisinin-susceptible diseases. PMID:25678989

Screening of a library of traditional Chinese medicines to identify anti-malarial compounds and extracts.

PubMed

Nonaka, Motohiro; Murata, Yuho; Takano, Ryo; Han, Yongmei; Bin Kabir, Md Hazzaz; Kato, Kentaro

2018-06-25

Malaria is a major infectious disease in the world. In 2015, approximately 212 million people were infected and 429,000 people were killed by this disease. Plasmodium falciparum, which causes falciparum malaria, is becoming resistant to artemisinin (ART) in Southeast Asia; therefore, new anti-malarial drugs are urgently needed. Some excellent anti-malarial drugs, such as quinine or ART, were originally obtained from natural plants. Hence, the authors screened a natural product library comprising traditional Chinese medicines (TCMs) to identify compounds/extracts with anti-malarial effects. The authors performed three assays: a malaria growth inhibition assay (GIA), a cytotoxicity assay, and a malaria stage-specific GIA. The malaria GIA revealed the anti-malarial ability and half-maximal inhibitory concentrations (IC 50 ) of the natural products, whereas the malaria stage-specific GIA revealed the point in the malaria life cycle where the products exerted their anti-malarial effects. The toxicity of the products to the host cells was evaluated with the cytotoxicity assay. Four natural compounds (berberine chloride, coptisine chloride, palmatine chloride, and dehydrocorydaline nitrate) showed strong anti-malarial effects (IC 50  < 50 nM), and low cytotoxicity (cell viability > 90%) using P. falciparum 3D7 strain. Two natural extracts (Phellodendri cortex and Coptidis rhizoma) also showed strong antiplasmodial effects (IC 50  < 1 µg/ml), and low cytotoxicity (cell viability > 80%). These natural products also demonstrated anti-malarial capability during the trophozoite and schizont stages of the malaria life cycle. The authors identified four compounds (berberine chloride, coptisine chloride, palmatine chloride, and dehydrocorydaline nitrate) and two extracts (Phellodendri cortex and Coptidis rhizoma) with anti-malarial activity, neither of which had previously been described. The IC 50 values of the compounds were comparable to that of chloroquine and better than that of pyrimethamine. These compounds and extracts derived from TCMs thus show promise as potential future anti-malarial drugs.

Galactose-Anchored Gelatin Nanoparticles for Primaquine Delivery and Improved Pharmacokinetics: A Biodegradable and Safe Approach for Effective Antiplasmodial Activity against P. falciparum 3D7 and in Vivo Hepatocyte Targeting.

PubMed

Kumar, Hitesh; Gothwal, Avinash; Khan, Iliyas; Nakhate, Kartik T; Alexander, Amit; Ajazuddin; Singh, Vineeta; Gupta, Umesh

2017-10-02

Primaquine phosphate (PQ) is mainly used as a radical cure therapy to eradicate relapse of malaria at the liver stage, which is particularly caused by P. falciparum and P. vivax. In the present study, PQ-loaded galactosylated gelatin nanoparticles (Gel-LA-PQ-NPs) were formulated using a one-step desolvation technique. The mean particle size of Gel-LA-PQ-NPs was found to be 93.48 ± 6.36 nm with a zeta potential of 4.80 ± 0.20 mV having 69.90 ± 1.53% encapsulation efficiency. Electron microscopy demonstrated that the NPs were spherical in shape and uniformly distributed without any cluster formation. The in vitro release of PQ from Gel-LA-PQ-NPs has been facilitated in sustained manner, and the release was three times slower than the naïve drug. The prepared nanoparticles (Gel-LA-PQ-NPs) were significantly (p < 0.0001) less hemolytic than the pure drug PQ. The hematological ex vivo study further supported that the developed Gel-LA-PQ-NPs were safer than PQ. The in vitro antiplasmodium assay revealed that the IC 50 value against the blood stage of asexual P. falciparum 3D7 strains was significantly (p < 0.01) less (2.862 ± 0.103 μM) for Gel-LA-PQ-NPs than naïve PQ (3.879 ± 0.655 μM). In vivo pharmacokinetic parameters of Gel-LA-PQ-NPs such as half-life and AUC were significantly higher for Gel-LA-PQ-NPs, i.e., with higher bioavailability. Galactosylation of the NPs led to liver targeting of the PQ in animal studies. Approximately eight-fold higher accumulation of PQ was observed in liver compared to pure drug (i.e., PQ). Conclusively, the prepared galactosylated gelatin nanocarrier holds the promising potential and hepatic targetability of an antimalarial, maintaining its safety and biocompatibility.

Design, synthesis, antiviral bioactivity and three-dimensional quantitative structure-activity relationship study of novel ferulic acid ester derivatives containing quinazoline moiety.

PubMed

Wu, Zengxue; Zhang, Jian; Chen, Jixiang; Pan, Jianke; Zhao, Lei; Liu, Dengyue; Zhang, Awei; Chen, Jin; Hu, Deyu; Song, Baoan

2017-10-01

Ferulic acid and quinazoline derivatives possess good antiviral activities. In order to develop novel compounds with high antiviral activities, a series of ferulic acid ester derivatives containing quinazoline were synthesized and evaluated for their antiviral activities. Bioassays indicated that some of the compounds exhibited good antiviral activities in vivo against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV). One of the compounds demonstrated significant curative and protective activities against TMV and CMV, with EC 50 values of 162.14, 114.61 and 255.49, 138.81 mg L -1 , respectively, better than those of ningnanmycin (324.51, 168.84 and 373.88, 272.70 mg L -1 ). The values of q 2 and r 2 for comparative molecular field analysis and comparative molecular similarity index analysis in the TMV (0.508, 0.663 and 0.992, 0.930) and CMV (0.530, 0.626 and 0.997, 0.981) models presented good predictive abilities. Some of the title compounds demonstrated good antiviral activities. Three-dimensional quantitative structure-activity relationship models revealed that the antiviral activities depend on steric and electrostatic properties. These results could provide significant structural insights for the design of highly active ferulic acid derivatives. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

13 CFR 103.4 - What is “good cause” for suspension or revocation?

Code of Federal Regulations, 2012 CFR

2012-01-01

... unlawful or unethical activity is good cause for suspension or revocation of the privilege to conduct... other unlawful or unethical activity, with respect to any matter involving SBA assistance. (b...

13 CFR 103.4 - What is “good cause” for suspension or revocation?

Code of Federal Regulations, 2014 CFR

2014-01-01

... unlawful or unethical activity is good cause for suspension or revocation of the privilege to conduct... other unlawful or unethical activity, with respect to any matter involving SBA assistance. (b...

13 CFR 103.4 - What is “good cause” for suspension or revocation?

Code of Federal Regulations, 2013 CFR

2013-01-01

... unlawful or unethical activity is good cause for suspension or revocation of the privilege to conduct... other unlawful or unethical activity, with respect to any matter involving SBA assistance. (b...

13 CFR 103.4 - What is “good cause” for suspension or revocation?

Code of Federal Regulations, 2011 CFR

2011-01-01

... unlawful or unethical activity is good cause for suspension or revocation of the privilege to conduct... other unlawful or unethical activity, with respect to any matter involving SBA assistance. (b...

Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists.

PubMed

Fujimoto, Tatsuhiko; Kunitomo, Jun; Tomata, Yoshihide; Nishiyama, Keiji; Nakashima, Masato; Hirozane, Mariko; Yoshikubo, Shin-Ichi; Hirai, Keisuke; Marui, Shogo

2011-11-01

During our efforts to identify a series of potent, selective, orally active human Orexin-2 Receptor (OX2R) antagonists, we elucidated structure-activity relationship (SAR) on the 7-position of a benzoxazepine scaffold by utilizing Hammett σ(p) and Hansch-Fujita π value as aromatic substituent constants. The attempts led to the discovery of compound 1m, possessing good in vitro potency with over 100-fold selectivity against OX1R, good metabolic stability in human and rat liver microsome, good oral bioavailability in rats, and in vivo antagonistic activity in rats by oral administration. Copyright © 2011 Elsevier Ltd. All rights reserved.

29 CFR 779.105 - Employees engaged in activities “closely related” and “directly essential” to the production of...

Code of Federal Regulations, 2014 CFR

2014-07-01

... âdirectly essentialâ to the production of goods for commerce. 779.105 Section 779.105 Labor Regulations... Engaged in Commerce Or in the Production of Goods for Commerce § 779.105 Employees engaged in activities “closely related” and “directly essential” to the production of goods for commerce. Some employees are...

29 CFR 779.105 - Employees engaged in activities “closely related” and “directly essential” to the production of...

Code of Federal Regulations, 2012 CFR

2012-07-01

... âdirectly essentialâ to the production of goods for commerce. 779.105 Section 779.105 Labor Regulations... Engaged in Commerce Or in the Production of Goods for Commerce § 779.105 Employees engaged in activities “closely related” and “directly essential” to the production of goods for commerce. Some employees are...

29 CFR 779.105 - Employees engaged in activities “closely related” and “directly essential” to the production of...

Code of Federal Regulations, 2013 CFR

2013-07-01

... âdirectly essentialâ to the production of goods for commerce. 779.105 Section 779.105 Labor Regulations... Engaged in Commerce Or in the Production of Goods for Commerce § 779.105 Employees engaged in activities “closely related” and “directly essential” to the production of goods for commerce. Some employees are...

Dissection of a Truth Regime: The Narrowing Effects on the Public Good of Neoliberal Discourse in the Virginia Performance-Based Funding Policy

ERIC Educational Resources Information Center

Letizia, Angelo J.

2016-01-01

A major role of all public higher education institutions is to foster the public good. In democratic societies, the public good emphasizes the more collective activities and benefits and how resources are accessible to all in a society. Institutions of higher education create new knowledge, promote cultural tolerance, increase civic activity, and…

IMMUNO-MODULATORY PROPERTIES OF PREBIOTICS EXTRACTED FROM vernonia amygdalina.

PubMed

Im, Ezeonu; Ae, Asuquo; Bn, Ukwah; Po, Ukoha

2016-01-01

Vernonia amygdalina , commonly called bitter-leaf, is widely consumed in many parts of Africa, and Nigeria, in particular. The leaf extract has been reported to have antimicrobial, anti-plasmodial, anti-helminthic, as well as prebiotic properties, but its immuno-modulatory effects have not been well-studied, neither have the prebiotics been identified. This study evaluated the immuno-modulatory properties of the aqueous leaf extract and identified the prebiotic components. The immuno-modulatory potential was evaluated by monitoring the effects of oral administration of the extract on immunological, haematological and lipid profiles of Rattus norvegicus , while the prebiotic components were identified by thin layer chromatography (TLC), following liquid-liquid fractionation of the extract. Consumption of the extract caused significant increases in CD4+-, white blood cell-, total lymphocyte- and high density lipid (HDL) counts; decreases in low density lipid (LDL) and triglycerides and no significant effect on haemoglobin (Hb) and packed cell volume (PCV) in the blood of test animals. The water-soluble fraction of the extract contained most of the phyto-constituents of the extract and Thin Layer Chromatographic analysis of the fraction revealed the presence of fructo-oligosaccharide and galacto-oligosaccharide prebiotics. The results from this study have shown that the aqueous leaf extract of V. amygdalina has positive immune-modulatory and haematologic effects and contains some important prebiotic compounds.

Antimicrobial and anticancer activity of some novel fluorinated thiourea derivatives carrying sulfonamide moieties: synthesis, biological evaluation and molecular docking.

PubMed

Ghorab, Mostafa M; Alsaid, Mansour S; El-Gaby, Mohamed S A; Elaasser, Mahmoud M; Nissan, Yassin M

2017-04-07

Various thiourea derivatives have been used as starting materials for compounds with better biological activities. Molecular modeling tools are used to explore their mechanism of action. A new series of thioureas were synthesized. Fluorinated pyridine derivative 4a showed the highest antimicrobial activity (with MIC values ranged from 1.95 to 15.63 µg/mL). Interestingly, thiadiazole derivative 4c and coumarin derivative 4d exhibited selective antibacterial activities against Gram positive bacteria. Fluorinated pyridine derivative 4a was the most active against HepG2 with IC50 value of 4.8 μg/mL. Molecular docking was performed on the active site of MK-2 with good results. Novel compounds were obtained with good anticancer and antibacterial activity especially fluorinated pyridine derivative 4a and molecular docking study suggest good activity as mitogen activated protein kinase-2 inhibitor. Graphical abstract Compound 4a in the active site of MK-2.

Is daily routine important for sleep? An investigation of social rhythms in a clinical insomnia population.

PubMed

Moss, Taryn G; Carney, Colleen E; Haynes, Patricia; Harris, Andrea L

2015-02-01

Social rhythms, also known as daily routines (e.g. exercise, of school or work, recreation, social activities), have been identified as potential time cues to help to regulate the biological clock. Past research has shown links between regularity and healthy sleep. This study examined the regularity and frequency of daytime activities in a clinical insomnia population and a good sleeper comparison group. Participants (N = 69) prospectively monitored their sleep and daily activities for a 2-week period. Although participants with insomnia and good sleepers had similar levels of activity, relative to good sleepers, those with insomnia were less regular in their activities. Findings from this study add to the growing number of studies that highlight the relative importance of the regularity of daytime activities on sleep. Accordingly, future research should test treatment components that focus on regulating daytime activities, which would likely improve treatment outcomes.

29 CFR 776.3 - Persons engaging in both covered and noncovered activities.

Code of Federal Regulations, 2010 CFR

2010-07-01

... activities. The Act applies to employees “engaged in commerce or in the production of goods for commerce..., volume, or amount of activities of either employee or employer which constitute engaging in commerce or in the production of goods for commerce. Sections 6 and 7 refer to “each” and “any” employee so...

Transforming a School Learning Exercise into a Public Engagement Event: "The Good, the Bad and the Algae"

ERIC Educational Resources Information Center

Redfern, James; Burdass, Dariel; Verran, Joanna

2013-01-01

School science laboratory classes and hands-on public engagement activities share many common aims and objectives in terms of science learning and literacy. This article describes the development and evaluation of a microbiology public engagement activity, "The Good, the Bad and the Algae", from a school laboratory activity. The school…

Antibacterial activity of Hygrophila stricta and Peperomia pellucida.

PubMed

Khan, M R; Omoloso, A D

2002-06-01

The crude methanolic extracts of Hygrophila scricta and Peperomia pellucida were fractionated into petrol, dichloromethane, ethyl acetate and butanol. All the crude extracts and the fractions exhibited a very good level of broad spectrum antibacterial activity. The fractions were more active than the crude extracts. The petrol fraction of H. stricta and the butanol fraction of P. pellucida were particularly good. No activity was noticed for the moulds tested.

Active Citizens, Good Citizens, and Insouciant Bystanders: The Educational Implications of Chinese University Students' Civic Participation via Social Networking

ERIC Educational Resources Information Center

Ke, Lin; Starkey, Hugh

2014-01-01

This virtual ethnographic study explores how Chinese university students use social network sites (SNSs) to participate in civic activities. An ideal of "active" citizens is contrasted with good citizens (Crick) and insouciant bystanders. We find that students engage with the civic issues embedded in everyday life; their online civic…

Sharing Good Practices: Teenage Girls, Sport, and Physical Activities.

ERIC Educational Resources Information Center

Vescio, Johanna A.; Crosswhite, Janice J.

2002-01-01

Investigated initiatives to increase teenage girls' participation in sport and physical activities, examining good practice case studies from Australia. Surveys of national, state, and regional sporting organizations and various community and school organizations (including culturally diverse girls and girls with disabilities) highlighted three…

In Vitro Assessment of Bioactivities of Lactobacillus Strains as Potential Probiotics for Humans and Chickens.

PubMed

Shokryazdan, P; Jahromi, M F; Liang, J B; Sieo, C C; Kalavathy, R; Idrus, Z; Ho, Y W

2017-11-01

Twelve previously isolated Lactobacillus strains were investigated for their in vitro bioactivities, including bile salt hydrolase (BSH), cholesterol-reducing and antioxidant activities, cytotoxic effects against cancer cells, enzyme activity, and biogenic amine production. Among them, only 4 strains showed relatively high BSH activity, whereas the rest exhibited low BSH activity. All 12 strains showed cholesterol-reducing and antioxidant activities, especially in their intact cells, which in most of the cases, the isolated strains were stronger in these activities than the tested commercial reference strains. None of the tested strains produced harmful enzymes (β-glucosidase and β-glucuronidase) or biogenic amines. Among the 12 strains, 3 strains were tested for their cytotoxic effects against 3 cancer cell lines, which exhibited strong cytotoxic effects, and they also showed selectivity in killing cancer cells when compared to normal cells. Hence, all 12 Lactobacillus strains could be considered good potential probiotic candidates because of their beneficial functional bioactivities. The Lactobacillus strains tested in this study could be considered good potential probiotic candidates for food/feed industry because of their beneficial functional bioactivities such as good cholesterol-reducing ability, high antioxidant activity, and good and selective cytotoxic effect against cancer cells. © 2017 Institute of Food Technologists®.

Ethnomedicinal survey of plants used in the treatment of malaria in Southern Nigeria.

PubMed

Iyamah, P C; Idu, M

2015-09-15

Malaria is one of the most severe public health problems worldwide. It is a leading cause of death and disease in many developing countries, where young children and pregnant women are the groups most affected. Spread of multidrug-resistant strains of Plasmodium and the adverse side effects of the existing anti-malarial drugs have necessitated the search for novel, well tolerated and more efficient antimalarial drugs. This ethnomedicinal study surveyed the different types of medicinal plants used for the treatment of malaria in Southern Nigeria with the intent of identifying plants that are traditionally employed in the treatment of malaria across geopolitical boundaries. Data were collected from 79 respondents composed of 50 traditional herbsellers and 29 herbal practitioners using a semi-structured questionnaire. Data was analyzed using frequency and percentages. Of the 79 respondents interviewed, 24% were males while 76% were females. A total of 156 species belonging to 60 families were reported being used to treat malaria in the study area. Fabaceae was the most represented family having fourteen (14) plant species. Of the plants identified during the survey, Azadirachta indica was the species of highest relative frequency of citation (RFC - 1.0). The dominant plant parts used in the preparation of remedies were leaves (50.50%) and Decoction was the main method of preparation. Analysis of regional plant occurrence revealed that South-Western Nigeria represented the region with the highest plant occurrence (60.7%) followed by South-South (24%) and South-East (15.3%). Regional occurrence of plants used in the treatment of malaria in Southern Nigeria is reported here for the first time. This study has documented a great diversity of plants used in the treatment of malaria in Southern Nigeria. Extracts prepared strictly according to the practitioners' recipes should therefore be screened for antiplasmodial activity and toxicity by in vitro and in vivo standard tests to justify their local usage. These studies might lead to the isolation and possible identification of potentially active compounds, which may be regarded as future promising phytomedicines in the treatment of malaria. Conservation of these plant species is also recommended to ensure their continuous availability for future use. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

In vivo antimalarial activity of crude extracts and solvent fractions of leaves of Strychnos mitis in Plasmodium berghei infected mice.

PubMed

Fentahun, Selamawit; Makonnen, Eyasu; Awas, Tesfaye; Giday, Mirutse

2017-01-05

Malaria is a major public health problem in the world which is responsible for death of millions particularly in sub-Saharan Africa. Today, the control of malaria has become gradually more complex due to the spread of drug-resistant parasites. Medicinal plants are the unquestionable source of effective antimalarials. The present study aimed to evaluate antiplasmodial activity and acute toxicity of the plant Strychnos mitis in Plasmodium berghei infected mice. Standard procedures were employed to investigate acute toxicity and 4-day suppressive effect of crude aqueous and hydro-methanolic extracts of the leaves of Strychnos mitis against P. berghei in Swiss albino mice. Water, n-hexane and chloroform fractions, obtained from crude hydro-methanolic extract, were also tested for their suppressive effect against P. berghei. All crude extracts revealed no obvious acute toxicity in mice up to the highest dose administered (2000 mg/kg). All crude and solvent fractions of the leaves of Strychnos mitis inhibited parasitaemia significantly (p < 0.01). At the highest dose of 600 mg/kg, both aqueous and hydro-methanolic extracts demonstrated higher performance with 95.5 and 93.97% parasitaemia suppression, respectively. All doses of crude extracts and fractions of leaves of Strychnos mitis prolonged survival time of infected mice dose dependently. The highest two doses of the crude aqueous and hydro-methanolic extracts, and chloroform and aqueous fractions prevented weight loss in a dose dependent manner. Whereas, all doses of n-hexane fraction prevented loss of body weight but not in a dose dependent manner. The crude aqueous extract at the doses of 400 mg/kg and 600 mg/kg and hydro-methanolic extract at all dose levels significantly (p < 0.01) prevented packed cell volume reduction. Crude aqueous extract at a dose of 600 mg/kg and hydro-methanolic extract at all dose levels significantly prevented temperature reduction. Phytochemical screening of the crude aqueous and hydro-methanolic extracts revealed the presence of alkaloids, anthraquinones, glycosides, terpenoids, saponins, tannins and phenols. The results of this study provide support the traditional therapeutic use of Strychnos mitis for treatment of malaria. However, further in-depth study is needed to evaluate the potential of the plant towards the development of new antimalarial agent.

Factors influencing mode of transport in older adolescents: a qualitative study

PubMed Central

2013-01-01

Background Since a decline in activity levels occurs in adolescence, active transport could be important to increase daily physical activity in older adolescents (17–18 years). To promote active transport, it is necessary to be aware of the barriers and facilitators of this type of transport, but also of other transport modes. This study sought to uncover the factors influencing the choice of transport mode for short distance travel to various destinations in older adolescents using focus groups. Methods Thirty-two focus group volunteers (mean age of 17 ± 1.2 years) were recruited from the two final years of the secondary school in Antwerp (Belgium). Five focus groups were conducted (five to eight participants/group). Content analysis was performed using NVivo 9 software (QSR International). Grounded theory was used to derive categories and subcategories. Results Data were categorized in three main themes with several subcategories: personal factors (high autonomy, low costs and health), social factors (good social support) and physical environmental factors (short travel time, good access to transport modes and to facilities, good weather, an adapted built environment, perceived safety and ecology). Conclusions For older adolescents, the interplay between short travel time, high autonomy, good social support, low costs, good access to transport modes and facilities, and good weather was important for choosing active transport over other transport forms for travelling short distances to various destinations. Other well-known factors such as safety, ecology and health seemed not to have a big influence on their transport mode choice. PMID:23574974

77 FR 98 - Commission Information Collection Activities, Proposed Collection (FERC-716); Comment Request...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-03

... requirements of FERC-716 (``Good Faith Request for Transmission Service and Response by Transmitting Utility..., provide standards by which the Commission determines if and when a valid good faith request for... 12 components of a good faith estimate and 5 components of a reply to a good faith request. Action...

41 CFR 101-25.103-4 - Disposition of promotional materials, trading stamps, or bonus goods.

Code of Federal Regulations, 2011 CFR

2011-07-01

... promotional materials, trading stamps, or bonus goods. 101-25.103-4 Section 101-25.103-4 Public Contracts and... materials, trading stamps, or bonus goods. (a) Agencies shall, through the lowest appropriate activity, arrange for transfer of promotional materials, trading stamps, or bonus goods, without reimbursement in...

41 CFR 101-25.103-4 - Disposition of promotional materials, trading stamps, or bonus goods.

Code of Federal Regulations, 2012 CFR

2012-07-01

... promotional materials, trading stamps, or bonus goods. 101-25.103-4 Section 101-25.103-4 Public Contracts and... materials, trading stamps, or bonus goods. (a) Agencies shall, through the lowest appropriate activity, arrange for transfer of promotional materials, trading stamps, or bonus goods, without reimbursement in...

41 CFR 101-25.103-4 - Disposition of promotional materials, trading stamps, or bonus goods.

Code of Federal Regulations, 2013 CFR

2013-07-01

... promotional materials, trading stamps, or bonus goods. 101-25.103-4 Section 101-25.103-4 Public Contracts and... materials, trading stamps, or bonus goods. (a) Agencies shall, through the lowest appropriate activity, arrange for transfer of promotional materials, trading stamps, or bonus goods, without reimbursement in...

41 CFR 101-25.103-4 - Disposition of promotional materials, trading stamps, or bonus goods.

Code of Federal Regulations, 2014 CFR

2014-07-01

... promotional materials, trading stamps, or bonus goods. 101-25.103-4 Section 101-25.103-4 Public Contracts and... materials, trading stamps, or bonus goods. (a) Agencies shall, through the lowest appropriate activity, arrange for transfer of promotional materials, trading stamps, or bonus goods, without reimbursement in...

41 CFR 101-25.103-4 - Disposition of promotional materials, trading stamps, or bonus goods.

Code of Federal Regulations, 2010 CFR

2010-07-01

... promotional materials, trading stamps, or bonus goods. 101-25.103-4 Section 101-25.103-4 Public Contracts and... materials, trading stamps, or bonus goods. (a) Agencies shall, through the lowest appropriate activity, arrange for transfer of promotional materials, trading stamps, or bonus goods, without reimbursement in...

75 FR 43997 - Agency Information Collection Activities: Transportation Entry and Manifest of Goods Subject to...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-27

... Activities: Transportation Entry and Manifest of Goods Subject to CBP Inspection and Permit AGENCY: U.S... agencies to comment on an information collection requirement concerning the: Transportation Entry and... CBP is soliciting comments concerning the following information collection: Title: Transportation...

Activity of Posaconazole and Other Antifungal Agents against Mucorales Strains Identified by Sequencing of Internal Transcribed Spacers▿

PubMed Central

Alastruey-Izquierdo, Ana; Castelli, Maria Victoria; Cuesta, Isabel; Monzon, Araceli; Cuenca-Estrella, Manuel; Rodriguez-Tudela, Juan Luis

2009-01-01

The antifungal susceptibility profiles of 77 clinical strains of Mucorales species, identified by internal transcribed spacer sequencing, were analyzed. MICs obtained at 24 and 48 h were compared. Amphotericin B was the most active agent against all isolates, except for Cunninghamella and Apophysomyces isolates. Posaconazole also showed good activity for all species but Cunninghamella bertholletiae. Voriconazole had no activity against any of the fungi tested. Terbinafine showed good activity, except for Rhizopus oryzae, Mucor circinelloides, and Rhizomucor variabilis isolates. PMID:19171801

Activity of posaconazole and other antifungal agents against Mucorales strains identified by sequencing of internal transcribed spacers.

PubMed

Alastruey-Izquierdo, Ana; Castelli, Maria Victoria; Cuesta, Isabel; Monzon, Araceli; Cuenca-Estrella, Manuel; Rodriguez-Tudela, Juan Luis

2009-04-01

The antifungal susceptibility profiles of 77 clinical strains of Mucorales species, identified by internal transcribed spacer sequencing, were analyzed. MICs obtained at 24 and 48 h were compared. Amphotericin B was the most active agent against all isolates, except for Cunninghamella and Apophysomyces isolates. Posaconazole also showed good activity for all species but Cunninghamella bertholletiae. Voriconazole had no activity against any of the fungi tested. Terbinafine showed good activity, except for Rhizopus oryzae, Mucor circinelloides, and Rhizomucor variabilis isolates.

Leisure time physical activity among pregnant women and its associations with maternal characteristics and pregnancy outcomes.

PubMed

Lindqvist, Maria; Lindkvist, Marie; Eurenius, Eva; Persson, Margareta; Ivarsson, Anneli; Mogren, Ingrid

2016-10-01

Physical activity during pregnancy is generally considered safe and beneficial for both the pregnant woman and her fetus. The overall aim was to investigate pregnant women's pre-pregnancy and early pregnancy physical activity and its associations with maternal characteristics and pregnancy outcomes. This cross-sectional study combined data from the Maternal Health Care Register in Västerbotten (MHCR-VB) and the Salut Programme Register (Salut-R). Data were collected from 3,868 pregnant women living in northern Sweden between 2011 and 2012. Almost half of the participants (47.1%) achieved the recommended level of physical activity. Compared to the women who did not achieve the recommended level of exercise, these women had lower BMI, very good or good self-rated health, and a higher educational level. No significant associations could be established between physical activity levels and GDM, birth weight, or mode of delivery. Positively, a considerably high proportion of Swedish pregnant women achieved the recommended level of physical activity. Factors associated with recommended physical activity level were BMI ≤30 kg/m(2), very good or good self-rated health, and higher educational level. Our findings emphasize the need for health care professionals to early detect and promote fertile and pregnant women towards health-enhancing physical activity, especially those with low levels of physical activity and overweight/obesity, to improve overall health in this population. Copyright © 2016 The Author(s). Published by Elsevier B.V. All rights reserved.

Differences in autonomic physiological responses between good and poor inductive reasoners.

PubMed

Melis, C; van Boxtel, A

2001-11-01

We investigated individual- and task-related differences in autonomic physiological responses induced by time limited figural and verbal inductive reasoning tasks. In a group of 52 participants, the percentage of correctly responded task items was evaluated together with nine different autonomic physiological response measures and respiration rate (RR). Weighted multidimensional scaling analyses of the physiological responses revealed three underlying dimensions, primarily characterized by RR, parasympathetic, and sympathetic activity. RR and sympathetic activity appeared to be relatively more important response dimensions for poor reasoners, whereas parasympathetic responsivity was relatively more important for good reasoners. These results suggest that poor reasoners showed higher levels of cognitive processing intensity than good reasoners. Furthermore, for the good reasoners, the dimension of sympathetic activity was relatively more important during the figural than during the verbal reasoning task, which was explained in terms of hemispheric lateralization in autonomic function.

Antimalarial, antimicrobial, cytotoxic, DNA interaction and SOD like activities of tetrahedral copper(II) complexes

NASA Astrophysics Data System (ADS)

Mehta, Jugal V.; Gajera, Sanjay B.; Patel, Mohan N.

2015-02-01

The mononuclear copper(II) complexes with P, O-donor ligand and different fluoroquinolones have been synthesized and characterized by elemental analysis, electronic spectra, TGA, EPR, FT-IR and LC-MS spectroscopy. An antimicrobial efficiency of the complexes has been tested against five different microorganisms in terms of minimum inhibitory concentration (MIC) and displays very good antimicrobial activity. The binding strength and binding mode of the complexes with Herring Sperm DNA (HS DNA) have been investigated by absorption titration and viscosity measurement studies. The studies suggest the classical intercalative mode of DNA binding. Gel electrophoresis assay determines the ability of the complexes to cleave the supercoiled form of pUC19 DNA. Synthesized complexes have been tested for their SOD mimic activity using nonenzymatic NBT/NADH/PMS system and found to have good antioxidant activity. All the complexes show good cytotoxic and in vitro antimalarial activities.

Muscle strength and physical activity are associated with self-rated health in an adult Danish population.

PubMed

Hansen, Andreas W; Beyer, Nina; Flensborg-Madsen, Trine; Grønbæk, Morten; Helge, Jørn W

2013-12-01

To describe associations of muscle strength, physical activity and self-rated health. Isometric muscle strength by maximal handgrip strength (HGS) or muscle strength by 30s repeated chair stand test (30s-CS) was combined with leisure time physical activity. Using logistic regression odds ratio was calculated for good self-rated health according to the combined associations among 16,539 participants (59.7% women), mean age 51.9 (SD: 13.8) years, from a cross-sectional study in Denmark 2007-2008. Good self-rated health was positively associated with higher levels of physical activity and greater muscle strength. Regarding HGS the highest OR for good self-rated health was in the moderate/vigorous physically active participants with high HGS (OR=6.84, 95% CI: 4.85-9.65 and OR=7.34, 95% CI: 5.42-9.96 for men and women, respectively). Similarly the highest OR for good self-rated health was in the moderate/vigorous physically active participants with high scores in the 30s-CS test (6.06, 95% CI: 4.32-8.50 and 13.38, 95% CI: 9.59-18.67 for men and women, respectively). The reference groups were sedentary participants with low strength (HGS or 30s-CS). The combined score for physical activity level with either HGS or 30s-CS was strongly positively associated with self-related health. © 2013.

29 CFR 779.104 - Employees “engaged in the production of goods for commerce.”

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 3 2012-07-01 2012-07-01 false Employees âengaged in the production of goods for commerce... Apply: Basic Principles and Individual Coverage Employees Engaged in Commerce Or in the Production of Goods for Commerce § 779.104 Employees “engaged in the production of goods for commerce.” The activities...

29 CFR 779.104 - Employees “engaged in the production of goods for commerce.”

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 3 2014-07-01 2014-07-01 false Employees âengaged in the production of goods for commerce... Apply: Basic Principles and Individual Coverage Employees Engaged in Commerce Or in the Production of Goods for Commerce § 779.104 Employees “engaged in the production of goods for commerce.” The activities...

29 CFR 779.104 - Employees “engaged in the production of goods for commerce.”

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 3 2013-07-01 2013-07-01 false Employees âengaged in the production of goods for commerce... Apply: Basic Principles and Individual Coverage Employees Engaged in Commerce Or in the Production of Goods for Commerce § 779.104 Employees “engaged in the production of goods for commerce.” The activities...

Pharmacophore Modelling and Synthesis of Quinoline-3-Carbohydrazide as Antioxidants

PubMed Central

El Bakkali, Mustapha; Ismaili, Lhassane; Tomassoli, Isabelle; Nicod, Laurence; Pudlo, Marc; Refouvelet, Bernard

2011-01-01

From well-known antioxidants agents, we developed a first pharmacophore model containing four common chemical features: one aromatic ring and three hydrogen bond acceptors. This model served as a template in virtual screening of Maybridge and NCI databases that resulted in selection of sixteen compounds. The selected compounds showed a good antioxidant activity measured by three chemical tests: DPPH radical, OH° radical, and superoxide radical scavenging. New synthetic compounds with a good correlation with the model were prepared, and some of them presented a good antioxidant activity. PMID:25954520

The effect of Berberine on the secondary structure of human serum albumin

NASA Astrophysics Data System (ADS)

Li, Ying; He, WenYing; Tian, Jianniao; Tang, Jianghong; Hu, Zhide; Chen, Xingguo

2005-05-01

The presence of several high affinity binding sites on human serum albumin (HSA) makes it a possible target for many drugs. This study is designed to examine the effect of Berberine (an ancient Chinese drug used for antimicrobial, antiplasmodial, antidiarrheal and cardiovascular) on the solution structure of HSA using fluorescence, Fourier transform infrared (FT-IR), circular dichroism (CD) spectroscopic methods. The fluorescence spectroscopic results show that the fluorescence intensity of HSA was significantly decreased in the presence of Berberine. The Scatchard's plots indicated that the binding of Berberine to HSA at 296, 303, 318 K is characterized by one binding site with the binding constant is 4.071(±0.128)×10 4, 3.741(±0.089)×10 4, 3.454(±0.110)×10 4 M -1, respectively. The protein conformation is altered (FT-IR and CD data) with reductions of α-helices from 54 to 47% for free HSA to 45-32% and with increases of turn structure5% for free HSA to 18% in the presence of Berberine. The binding process was exothermic, enthalpy driven and spontaneous, as indicated by the thermodynamic analyses, Berberine bound to HSA was mainly based on hydrophobic interaction and electrostatic interaction cannot be excluded from the binding. Furthermore, the displace experiments indicate that Berberine can bind to the subdomain IIA, that is, high affinity site (site II).

In vitro and ex vivo activity of an Azadirachta indica A.Juss. seed kernel extract on early sporogonic development of Plasmodium in comparison with azadirachtin A, its most abundant constituent.

PubMed

Dahiya, Nisha; Chianese, Giuseppina; Abay, Solomon Mequanente; Taglialatela-Scafati, Orazio; Esposito, Fulvio; Lupidi, Giulio; Bramucci, Massimo; Quassinti, Luana; Christophides, George; Habluetzel, Annette; Lucantoni, Leonardo

2016-12-15

NeemAzal ® (NA) is a quantified extract from seed kernels of neem, Azadirachta indica A.Juss. (Meliaceae), with a wide spectrum of biological properties, classically ascribed to its limonoid content. NA contains several azadirachtins (A to L), azadirachtin A (AzaA) being its main constituent. AzaA has been shown to inhibit microgamete formation of the rodent malaria parasite Plasmodium berghei, and NA was found to completely inhibit the transmission of Plasmodium berghei to Anopheles stephensi mosquitoes when administered to gametocytemic mice at a corresponding AzaA dose of 50mg/kg before exposure to mosquitoes. The present study was aimed at i) assessing the pharmacodynamics and duration of action of NA and AzaA against P. berghei exflagellation in systemic circulation in mice and ii) elucidating the transmission blocking activity (TBA) of the main NA constituents. The NA and AzaA pharmacodynamics on exflagellation were assessed through ex vivo exflagellation assays, while TBA of NA constituents was evaluated through in vitro ookinete development assay. Pharmacodynamics experiments: Peripheral blood from P. berghei infected BALB/c mice with circulating mature gametocytes, were treated i.p. with 50mg/kg and 100mg/kg pure AzaA and with NeemAzal ® (Trifolio-M GmbH) at the corresponding AzaA concentrations. The effect magnitude and duration of action of compounds was estimated by counting exflagellation centers, formed by microgametocytes in process of releasing flagellated gametes, at various time points after treatment in ex vivo exflagellation tests. Ookinete Development Assay: The direct effects of NeemAzal ® and AzaA on ookinete development were measured by fluorescence microscopy after incubation of gametocytemic blood with various concentrations of test substances in microplates for 24h. The exflagellation tests revealed an half-life of NA anti-plasmodial compounds of up to 7h at a NA dose corresponding to 100mg/kg equivalent dose of AzaA. The ookinete development assay showed an increased activity of NA against early sporogonic stages compared to that of AzaA. The IC 50 value determined for NA was 6.8µg/ml (CI 95 : 5.95-7.86), about half of the AzaA IC 50 (12.4µg/ml; CI 95 : 11.0-14.04). The stronger activity of NA, when compared to AzaA, could not be explained by an additive or synergistic effect by other azadirachtins (B, D and I) present in NA. In fact, the addition of these compounds at 50µM concentration to AzaA did not evidence any decrease of the IC 50 against early sporogonic stages to that obtained with AzaA alone. It is likely that other non-limonoid compounds present in NA may contribute to AzaA activity and enhanced pharmacodynamics against exflagellation both in vitro and in vivo. Copyright © 2016. Published by Elsevier GmbH.

The effect of adding active flexion to modified Kleinert regime on outcomes for zone 1 to 3 flexor tendon repairs. A prospective randomized trial.

PubMed

Rigó, István Zoltán; Haugstvedt, Jan-Ragnar; Røkkum, Magne

2017-11-01

In a prospective randomized study, we studied whether adding active flexion to a modified Kleinert regime changed outcomes of flexor tendon repairs in zone 1, 2 and 3 in 73 fingers (53 patients). Evaluation included active range of finger motion, grip and pinch strengths. Twelve months after surgery, the increase in range of active finger motion after adding active flexion was insignificant compared with that with the modified Kleinert regime. According to the Strickland criteria, 20 out of 29 fingers had excellent or good recovery after adding active flexion, as did 28 out of 34 fingers with the modified Kleinert regime; we could not detect significant improvement of the good and excellent rate. At 6 months, the pinch strength was significantly higher with the addition of active flexion. We failed to find that adding active finger flexion to the modified Kleinert regime improves the overall long-term results of repairs in zone 1 to 3, though recovery appeared faster, and the good and excellent recovery of zone 2 repairs was 17% greater with the active flexion protocol. I.

Design, synthesis and biological screening of some pyridinylpyrazole and pyridinylisoxazole derivatives as potential anti-inflammatory, analgesic, antipyretic and antimicrobial agents.

PubMed

El-Hawash, Soad A M; Soliman, Raafat; Youssef, Amal M; Ragab, Hanan M A; Elzahhar, Perihan A S; El-Ashmawey, Ibrahim M; Abdel Wahab, Abeer E; Shaat, Iman A

2014-05-01

A series of substituted pyridinylpyrazole (or isoxazole) derivatives were synthesized and evaluated for their anti-inflammatory (AI) activity using formalin-induced paw edema bioassays. Their inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) were also determined. The analgesic activity of the same compounds was evaluated using rat-tail withdrawal technique. Their antipyretic activity was also evaluated. The results revealed that compounds 4a,b, 6a, 8a, 14c and 15a exhibited significant AI and analgesic activities. Compounds 5a, 6a and 8a displayed good antipyretic activity. Compounds 14c and 15a showed good COX-2 inhibitory activity and weak inhibition of COX-1. Additionally, the most active compounds were shown to have a large safety margin (ALD50 >300-400 mg / Kg) and minimal ulcerogenic potentialities when administered orally at a dose of 300 mg/Kg. Docking studies for 14c and 15a with COX-2 showed good binding profile. Antimicrobial evaluation proved that most of the compounds exhibited distinctive activity against the gram negative bacteria, P. aeruginosa and E coli.

29 CFR 779.207 - Related activities in retail operations.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Sess. p. 41.) For example, in operations of a single retailing business a drug store may sell a large variety of different products, and a grocery store may sell clothing and furniture and other goods... store are “related activities,” even if the store sells a great variety of different types of goods and...

29 CFR 779.207 - Related activities in retail operations.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Sess. p. 41.) For example, in operations of a single retailing business a drug store may sell a large variety of different products, and a grocery store may sell clothing and furniture and other goods... store are “related activities,” even if the store sells a great variety of different types of goods and...

29 CFR 779.207 - Related activities in retail operations.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Sess. p. 41.) For example, in operations of a single retailing business a drug store may sell a large variety of different products, and a grocery store may sell clothing and furniture and other goods... store are “related activities,” even if the store sells a great variety of different types of goods and...

29 CFR 779.207 - Related activities in retail operations.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Sess. p. 41.) For example, in operations of a single retailing business a drug store may sell a large variety of different products, and a grocery store may sell clothing and furniture and other goods... store are “related activities,” even if the store sells a great variety of different types of goods and...

29 CFR 779.207 - Related activities in retail operations.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Sess. p. 41.) For example, in operations of a single retailing business a drug store may sell a large variety of different products, and a grocery store may sell clothing and furniture and other goods... store are “related activities,” even if the store sells a great variety of different types of goods and...

Leading a Community of Learners: Learning to Be Moral by Engaging the Morality of Learning

ERIC Educational Resources Information Center

Starratt, Robert J.

2007-01-01

This article attempts to provide a foundational understanding of school learning as moral activity as well as intellectual activity. It first develops a distinction between general ethics and professional ethics, and provides an initial explanation of the moral good involved in learning. The moral good of learning is then connected to the…

fMRI brain activation in patients with insomnia disorder during a working memory task.

PubMed

Son, Young-Don; Kang, Jae Myeong; Cho, Seong-Jin; Lee, Jung-Sun; Hwang, Hee Young; Kang, Seung-Gul

2018-05-01

This study used functional magnetic resonance imaging (fMRI) to investigate differences in the functional brain activation of patients with insomnia disorder (n = 21, mean age = 36.6) and of good sleepers (n = 26, mean age = 33.2) without other comorbidities or structural brain abnormalities during a working memory task. All participants completed a clinical questionnaire, were subjected to portable polysomnography (PSG), and performed the working memory task during an fMRI scan. The subjects who were suspected of major sleep disorder and comorbid psychiatric disorders except insomnia disorder were excluded. To compare the brain activation on working memory from the insomnia group with those from the good-sleeper group, a two-sample t test was performed. Statistical significance was determined using 3DClustSim with the updated algorithm to obtain a reasonable cluster size and p value for each analysis. We observed higher levels of brain activation in the right lateral inferior frontal cortex and the right superior temporal pole in the insomnia group compared to good sleepers (cluster-based multiple comparison correction, p < 0.001, k = 34 @ α = 0.01). Thus, patients with insomnia disorder showed increased brain activation during working memory relative to good sleepers, and this may be indicative of compensatory brain activation to maintain cognitive performance in patients with insomnia disorder without other comorbidities.

76 FR 55067 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-06

... Pharmaceutical Current Good Manufacturing Practice AGENCY: Food and Drug Administration, HHS. ACTION: Notice... Good Manufacturing Practice--(OMB Control Number 0910-0563)--Extension The guidance is intended to... products, on how to resolve disputes of scientific and technical issues relating to current good...

75 FR 44841 - Agency Information Collection Activities; Revision of a Currently-Approved Information Collection...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-29

... Request: Transportation of Household Goods; Consumer Protection AGENCY: Federal Motor Carrier Safety... request (ICR), ``Transportation of Household Goods; Consumer Protection,'' OMB Control Number 2126-0025...: Respondents: 8,500 [6,000 household goods movers + 2,500 consumers]. Issued on: July 23, 2010. Kelly Leone...

The Good Work.

ERIC Educational Resources Information Center

Csikszentmihalyi, Mihaly

2003-01-01

Examines the working lives of geneticists and journalists to place into perspective what lies behind personal ethics and success. Defines "good work" as productive activity that is valued socially and loved by people engaged in it. Asserts that certain cultural values, social controls, and personal standards are necessary to maintain good work and…

Patients’ conceptions of their own influence on good treatment response to biological therapy in chronic inflammatory arthritis

PubMed Central

Larsson, Ingrid

2017-01-01

Background Biological therapies are common in the treatment of patients with chronic inflammatory arthritis (CIA). However, despite the fact that many patients respond well to their biological therapies, there are still a number of nonresponders. In order to design the best care for patients, it is important to understand how they conceive their own role in their treatment response. Objective To explore how patients with CIA conceive their own influence on a good treatment response to biological therapy. Methods This study had an exploratory and descriptive design with a phenomenographic approach. Interviews were conducted with 25 patients (11 women and 14 men) aged 17–79 years, with CIA who were undergoing biological therapy and who had low disease activity or were in remission. Results Patients with CIA undergoing biological therapy conceived their own influence on good treatment response in terms of adherence, physical activity, mental attitude, social support, and self-awareness. Adherence was described as the foundation for the patients’ own influence on good treatment response. Physical activity, mental attitude, and social support reflected three essential ways of understanding patients’ influence on good treatment response where the patients spoke about physical strength, mental strength, and social strength. Self-awareness reflected a comprehensive way of influencing good treatment response in which patients balanced their physical, mental, and social resources in partnership with health care professionals. Conclusion Patients conceived that they had a responsibility for adhering to the treatment as well as achieving balance in life in order to ensure good treatment response. Self-awareness was essential for maintaining a good treatment response, and this reflected the patients’ awareness of the complexity of living their lives with a chronic illness. PMID:28706444

Patients' conceptions of their own influence on good treatment response to biological therapy in chronic inflammatory arthritis.

PubMed

Larsson, Ingrid

2017-01-01

Biological therapies are common in the treatment of patients with chronic inflammatory arthritis (CIA). However, despite the fact that many patients respond well to their biological therapies, there are still a number of nonresponders. In order to design the best care for patients, it is important to understand how they conceive their own role in their treatment response. To explore how patients with CIA conceive their own influence on a good treatment response to biological therapy. This study had an exploratory and descriptive design with a phenomenographic approach. Interviews were conducted with 25 patients (11 women and 14 men) aged 17-79 years, with CIA who were undergoing biological therapy and who had low disease activity or were in remission. Patients with CIA undergoing biological therapy conceived their own influence on good treatment response in terms of adherence, physical activity, mental attitude, social support, and self-awareness. Adherence was described as the foundation for the patients' own influence on good treatment response. Physical activity, mental attitude, and social support reflected three essential ways of understanding patients' influence on good treatment response where the patients spoke about physical strength, mental strength, and social strength. Self-awareness reflected a comprehensive way of influencing good treatment response in which patients balanced their physical, mental, and social resources in partnership with health care professionals. Patients conceived that they had a responsibility for adhering to the treatment as well as achieving balance in life in order to ensure good treatment response. Self-awareness was essential for maintaining a good treatment response, and this reflected the patients' awareness of the complexity of living their lives with a chronic illness.

[Identification of Good-Practice Projects in Promoting Physical Activity - Methods, Pitfalls and Sampled Outcomes].

PubMed

Henn, Annette; Karger, Claudia; Wöhlken, Katrin; Meier, Diana; Ungerer-Röhrich, Ulrike; Graf, Christine; Woll, Alexander

2017-03-01

The aim of this paper is to identify and show examples of good practice of public health promotion. For this, uniform quality criteria were worked out under consideration of national and international scientific literature.For the identification of examples of good practice, a comparison of different quality criteria was carried out and combined with each other in a first step. In the following step, examples of good practice were identified after a comprehensive search. The choice of the "good-practice" projects is exemplary and lays no claim to completeness.6 main quality criteria (QC) of programs promoting physical activity could be identified in the national and international context. The analysis showed altogether 10 projects which can exemplarily be classified as examples of good practice of the target groups of children and teenagers, adults, older people and people with pre-existing illnesses. These projects, however, show major differences in their (methodological) quality.The analysis reports a lack of "Good-Practice" examples. Deficits lie mainly in documentation and sustainability. Because of incomplete documentation, an assessment as a "Good-Practice" example is only possible to a limited extent; a lot of information, particularly in the evaluation, is missing. © Georg Thieme Verlag KG Stuttgart · New York.

Comparison of obese adults with poor versus good sleep quality during a functional neuroimaging delay discounting task: A pilot study.

PubMed

Martin, Laura E; Pollack, Lauren; McCune, Ashley; Schulte, Erica; Savage, Cary R; Lundgren, Jennifer D

2015-10-30

This study aimed to determine if obese adults with poor versus good sleep quality demonstrate reduced self-regulatory capacity and different patterns of neural activation when making impulsive monetary choices. Six obese, good quality sleepers (M age=44.7 years, M BMI=38.1 kg/m(2)) were compared to 13 obese, poor quality sleepers (M age=42.6, M BMI=39.2 kg/m(2)) on sleep and eating behavior and brain activation in prefrontal and insular regions while engaging in a delay discounting task during functional magnetic resonance imaging (fMRI). Poor quality sleepers demonstrated significantly lower brain activation in the right inferior frontal gyrus, right middle frontal gyrus, and bilateral insula when making immediate and smaller (impulsive) monetary choices compared to the baseline condition. Behaviorally, poor compared to good quality sleepers reported higher scores in the night eating questionnaire. Obese adults with poor sleep quality demonstrate decreased brain activation in multiple regions that regulate cognitive control and interceptive awareness, possibly reducing self-regulatory capacity when making immediately gratifying decisions. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Exercise: A Good Way to Fight Aging and Smoking | Smokefree 60+

Cancer.gov

Learn how to start an exercise routine that can help you feel and look younger AND stay quit! Health benefits of exercising No matter how old you are, regular physical activity can help you look younger and stay more fit than people who aren't active. Regular exercise can also be good medicine in your fight to stay off cigarettes. You will sleep better, be less likely to gain weight, and have more energy. Physical activity also helps to:

Deriving the reference value from the circadian motor active patterns in the "non-dementia" population, compared to the "dementia" population: What is the amount of physical activity conducive to the good circadian rhythm.

PubMed

Kodama, Ayuto; Kume, Yu; Tsugaruya, Megumi; Ishikawa, Takashi

2016-01-01

The circadian rhythm in older adults is commonly known to change with a decrease in physical activity. However, the association between circadian rhythm metrics and physical activity remains unclear. The objective of this study was to examine circadian activity patterns in older people with and without dementia and to determine the amount of physical activity conducive to a good circadian measurement. Circadian parameters were collected from 117 older community-dwelling people (66 subjects without dementia and 52 subjects with dementia); the parameters were measured continuously using actigraphy for 7 days. A receiver operating characteristic (ROC) curve was applied to determine reference values for the circadian rhythm parameters, consisting of interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA), in older subjects. The ROC curve revealed reference values of 0.55 for IS, 1.10 for IV, and 0.82 for RA. In addition, as a result of the ROC curve in the moderate-to-vigorous physical Activity (MVPA) conducive to the reference value of the Non-parametric Circadian Rhythm Analysis per day, the optimal reference values were 51 minutes for IV and 55 minutes for RA. However, the IS had no classification accuracy. Our results demonstrated the reference values derived from the circadian parameters of older Japanese population with or without dementia. Also, we determined the MVPA conducive to a good circadian rest-active pattern. This reference value for physical activity conducive to a good circadian rhythm might be useful for developing a new index for health promotion in the older community-dwelling population.

Translation, Cross-Cultural Adaptation, and Validation of the Activity Rating Scale for Disorders of the Knee.

PubMed

Flosadottir, Vala; Roos, Ewa M; Ageberg, Eva

2017-09-01

The Activity Rating Scale (ARS) for disorders of the knee evaluates the level of activity by the frequency of participation in 4 separate activities with high demands on knee function, with a score ranging from 0 (none) to 16 (pivoting activities 4 times/wk). To translate and cross-culturally adapt the ARS into Swedish and to assess measurement properties of the Swedish version of the ARS. Cohort study (diagnosis); Level of evidence, 2. The COSMIN guidelines were followed. Participants (N = 100 [55 women]; mean age, 27 years) who were undergoing rehabilitation for a knee injury completed the ARS twice for test-retest reliability. The Knee injury and Osteoarthritis Outcome Score (KOOS), Tegner Activity Scale (TAS), and modernized Saltin-Grimby Physical Activity Level Scale (SGPALS) were administered at baseline to validate the ARS. Construct validity and responsiveness of the ARS were evaluated by testing predefined hypotheses regarding correlations between the ARS, KOOS, TAS, and SGPALS. The Cronbach alpha, intraclass correlation coefficients, absolute reliability, standard error of measurement, smallest detectable change, and Spearman rank-order correlation coefficients were calculated. The ARS showed good internal consistency (α ≈ 0.96), good test-retest reliability (intraclass correlation coefficient >0.9), and no systematic bias between measurements. The standard error of measurement was less than 2 points, and the smallest detectable change was less than 1 point at the group level and less than 5 points at the individual level. More than 75% of the hypotheses were confirmed, indicating good construct validity and good responsiveness of the ARS. The Swedish version of the ARS is valid, reliable, and responsive for evaluating the level of activity based on the frequency of participation in high-demand knee sports activities in young adults with a knee injury.

Protection of people and environment from radiation risk through good regulatory practice

NASA Astrophysics Data System (ADS)

Jais, Azlina Mohammad; Hassan, Najwa

2017-01-01

The term "good regulatory practice" has seen growing frequency of usage worldwide, especially since the 2011 Fukushima nuclear incident. However, the term appears quite ambiguous as it may mean differently to different people. This leads us to the first important question: what does "good regulatory practice" actually mean? When used in conjunction with the Fukushima incident, do we imply that there is an absence of "good regulatory practice" in the Japanese' Nuclear and Industry Safety Agency (NISA)? This is quite troubling. It is clear that the term should be defined formally so that our understanding of "good regulatory practice" can be standardized. There is still another important question beyond agreeing on what "good regulatory practice" is: is "good regulatory practice" specific to a region, or is it global? And is it applicable only to nuclear regulators, or to all types of regulators per se? This paper aims to deliberate on the above mentioned questions. Specifically, we hope to discuss the "good regulatory practice" for atomic energy activities in order to protect the people and the environment from radiation risk of such activities. By understanding what "good regulatory practice" truly means, a newcomer country such as Malaysia can quickly learn and adopt these practices so as to assure a competent national nuclear regulatory authority who will be responsible in ensuring the safety, security and safeguards of peaceful atomic energy activities in the country including nuclear liability. In understanding this concept, a holistic approach will be taken by looking into example of advanced and newcomer countries of various nuclear regulatory authorities all around the world. Then the paper will focus on the challenges that the current nuclear regulatory authority in Malaysia which is Atomic Energy Licensing Board has, its challenges to follow the concept of "good regulatory practice" and its ways to overcome it. This study explore the initiatives could be considered by nuclear regulatory authority and the necessary criteria of an "ideal" how nuclear regulatory authority should implement the "good regulatory practice" approach.

Productivity and Capital Goods.

ERIC Educational Resources Information Center

Zicht, Barbara, Ed.; And Others

1981-01-01

Providing teacher background on the concepts of productivity and capital goods, this document presents 3 teaching units about these ideas for different grade levels. The grade K-2 unit, "How Do They Do It?," is designed to provide students with an understanding of how physical capital goods add to productivity. Activities include a field trip to…

Writing for Primary Science

ERIC Educational Resources Information Center

Mawby, Tara, Ed.

2011-01-01

In this article, two short pieces are presented to show educators just what a good article and a good review could have in them. This article has been written for the purpose of illustrating a good example, but is also representative of the type of content the editors encourage in "Primary Science": practical and active, with images. They also…

Can You Show You Are a Good Lecturer?

ERIC Educational Resources Information Center

Wood, Leigh N.; Harding, Ansie

2007-01-01

Measurement of the quality of teaching activities is becoming increasingly important since universities are rewarding performance in terms of promotion, awards and bonuses and research is no longer the only key performance indicator. Good teaching is not easy to identify and measure. This paper specifically deals with the issue of good teaching in…

Work injuries among drivers in the goods-transport branch in Denmark.

PubMed

Shibuya, Hitomi; Cleal, Bryan; Mikkelsen, Kim Lyngby

2008-05-01

Goods-transport drivers in Denmark had an elevated rate of hospital contact due to injury compared with the skilled/semiskilled workforce in general in recent years. There is a need to elucidate the causes of their work injuries. We analyzed the Danish National Work Injury Register for the 10-year period 1993-2002. The vast majority (92.6%) of the work injuries among goods-transport were sustained under non-traffic activities, that is, collecting, loading, unloading, and delivering goods. They fell from height (22.3%), suffered from overexertion (14.2%), got caught between/under objects (12.6%), collided with objects (12.0%), slipped/tripped (10.6%), or got struck by falling objects (9.0%). There is a clear need for efforts to prevent work injuries under non-traffic activities among goods-transport drivers in Denmark. For this end, it is necessary to involve not only the drivers' employers for reinforcement of safety procedures, but also the employers' customers for improvement of the physical environment, in which drivers collect, load, unload, and deliver goods. (c) 2008 Wiley-Liss, Inc.

Earthworm-mediated synthesis of silver nanoparticles: A potent tool against hepatocellular carcinoma, Plasmodium falciparum parasites and malaria mosquitoes.

PubMed

Jaganathan, Anitha; Murugan, Kadarkarai; Panneerselvam, Chellasamy; Madhiyazhagan, Pari; Dinesh, Devakumar; Vadivalagan, Chithravel; Aziz, Al Thabiani; Chandramohan, Balamurugan; Suresh, Udaiyan; Rajaganesh, Rajapandian; Subramaniam, Jayapal; Nicoletti, Marcello; Higuchi, Akon; Alarfaj, Abdullah A; Munusamy, Murugan A; Kumar, Suresh; Benelli, Giovanni

2016-06-01

The development of parasites and pathogens resistant to synthetic drugs highlighted the needing of novel, eco-friendly and effective control approaches. Recently, metal nanoparticles have been proposed as highly effective tools towards cancer cells and Plasmodium parasites. In this study, we synthesized silver nanoparticles (EW-AgNP) using Eudrilus eugeniae earthworms as reducing and stabilizing agents. EW-AgNP showed plasmon resonance reduction in UV-vis spectrophotometry, the functional groups involved in the reduction were studied by FTIR spectroscopy, while particle size and shape was analyzed by FESEM. The effect of EW-AgNP on in vitro HepG2 cell proliferation was measured using MTT assays. Apoptosis assessed by flow cytometry showed diminished endurance of HepG2 cells and cytotoxicity in a dose-dependent manner. EW-AgNP were toxic to Anopheles stephensi larvae and pupae, LC(50) were 4.8 ppm (I), 5.8 ppm (II), 6.9 ppm (III), 8.5 ppm (IV), and 15.5 ppm (pupae). The antiplasmodial activity of EW-AgNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. EW-AgNP IC(50) were 49.3 μg/ml (CQ-s) and 55.5 μg/ml (CQ-r), while chloroquine IC(50) were 81.5 μg/ml (CQ-s) and 86.5 μg/ml (CQ-r). EW-AgNP showed a valuable antibiotic potential against important pathogenic bacteria and fungi. Concerning non-target effects of EW-AgNP against mosquito natural enemies, the predation efficiency of the mosquitofish Gambusia affinis towards the II and II instar larvae of A. stephensi was 68.50% (II) and 47.00% (III), respectively. In EW-AgNP-contaminated environments, predation was boosted to 89.25% (II) and 70.75% (III), respectively. Overall, this research highlighted the EW-AgNP potential against hepatocellular carcinoma, Plasmodium parasites and mosquito vectors, with little detrimental effects on mosquito natural enemies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Efficacy and safety evaluation of a novel trioxaquine in the management of cerebral malaria in a mouse model.

PubMed

Odhiambo, Onyango C; Wamakima, Hannah N; Magoma, Gabriel N; Kirira, Peter G; Malala, Bonface J; Kimani, Francis T; Muregi, Francis W

2017-07-03

The emergence of multidrug-resistant strains of Plasmodium falciparum poses a great threat of increased fatalities in cases of cerebral and other forms of severe malaria infections in which parenteral artesunate monotherapy is the current drug of choice. The study aimed to investigate in a mouse model of human cerebral malaria whether a trioxaquine chemically synthesized by covalent linking of a 4,7-dichloroquinoline pharmacophore to artesunate through a recent drug development approach termed 'covalent bitherapy' could improve the curative outcomes in cerebral malaria infections. Human cerebral malaria rodent model, the C57BL/6 male mice were infected intraperitoneally (ip) with Plasmodium berghei ANKA and intravenously (iv) treated with the trioxaquine from day 8 post-infection (pi) at 12.5 and 25 mg/kg, respectively, twice a day for 3 days. Treatments with the trioxaquine precursors (artesunate and 4,7-dichloroquine), and quinine were also included as controls. In vivo safety evaluation for the trioxaquine was done according to Organization for Economic Co-operation and Development (OECD) guidelines 423, where female Swiss albino mice were orally administered with either 300 or 2000 mg/kg of the trioxaquine and monitored for signs of severity, and or mortality for 14 days post-treatment. The trioxaquine showed a potent and a rapid antiplasmodial activity with 80% parasite clearance in the first 24 h for the two dosages used. Long-term parasitaemia monitoring showed a total parasite clearance as the treated mice survived beyond 60 days post-treatment, with no recrudescence observed. Artesunate treated mice showed recrudescence 8 days post-treatment, with all mice in this group succumbing to the infection. Also, 4,7-dichloroquinoline and quinine did not show any significant parasitaemia suppression in the first 24 h post-treatment, with the animals succumbing to the infection. Covalent bitherapy proves to be a viable source of urgently needed new anti-malarials for management of cerebral malaria, and this polypharmacology approach could be a potential strategy to protect artesunate from parasite resistance and in potentially improving clinical outcomes in severe forms of malaria infections.

Sustained-release liquisolid compact tablets containing artemether-lumefantrine as alternate-day regimen for malaria treatment to improve patient compliance.

PubMed

Nnamani, Petra Obioma; Ugwu, Agatha Adaora; Ibezim, Emmanuel Chinedu; Kenechukwu, Franklin Chimaobi; Akpa, Paul Achile; Ogbonna, John-Dike Nwabueze; Obitte, Nicholas Chinedu; Odo, Amelia Ngozi; Windbergs, Maike; Lehr, Claus-Michael; Attama, Anthony Amaechi

The present study aimed to develop low-dose liquisolid tablets of two antimalarial drugs artemether-lumefantrine (AL) from a nanostructured lipid carrier (NLC) of lumefantrine (LUM) and estimate the potential of AL as an oral delivery system in malariogenic Wistar mice. LUM-NLCs were prepared by hot homogenization using Precirol ® ATO 5/Transcutol ® HP and tallow fat/Transcutol ® HP optimized systems containing 3:1 ratios of the lipids, respectively, as the matrices. LUM-NLC characteristics, including morphology, particle size, zeta potential, encapsulation efficiency, yield, pH-dependent stability, and interaction studies, were investigated. Optimized LUM-NLCs were mixed with artemether powder and other dry ingredients and the resultant powder evaluated for micromeritics. Subsequent AL liquisolid tablets were tested for in vitro drug release and in vivo antiplasmodial activity in mice infected with Plasmodium berghei berghei (NK 65). Results showed that optimized LUM-NLC were stable, spherical, polydispersed but nanometric. Percentage yield and encapsulation efficiency were ~92% and 93% for Precirol ® ATO 5/Transcutol ® HP batch, then 81% and 95% for tallow fat/Transcutol ® HP batch while LUM was amorphous in NLC matrix. In vitro AL release from liquisolid compacts revealed initial burst release and subsequent sustained release. Liquisolid tablet compacts formulated with Precirol ® ATO 5/Transcutol ® HP-AL4 achieved higher LUM release in simulated intestinal fluid (84.32%) than tallow fat/Transcutol ® HP-BL3 (77.9%). Non-Fickian (anomalous) diffusion and super case II transport were the predominant mechanisms of drug release. Equal parasitemia reduction was observed for both batches of tablet compacts (~92%), superior to the reduction obtained with commercial antimalarial formulations: Coartem ® tablets (86%) and chloroquine phosphate tablets (66%). No significant difference ( P <0.05) in parasite reduction between double (4/24 mg/kg) and single (2/12 mg/kg) strength doses of AL compacts was observed. Our result highlights that AL could be formulated in much lower doses (4/24 mg/kg), for once-in-two days oral administration to improve patient compliance, which is currently not obtainable with conventional AL dosage forms.

Sustained-release liquisolid compact tablets containing artemether–lumefantrine as alternate-day regimen for malaria treatment to improve patient compliance

PubMed Central

Nnamani, Petra Obioma; Ugwu, Agatha Adaora; Ibezim, Emmanuel Chinedu; Kenechukwu, Franklin Chimaobi; Akpa, Paul Achile; Ogbonna, John-Dike Nwabueze; Obitte, Nicholas Chinedu; Odo, Amelia Ngozi; Windbergs, Maike; Lehr, Claus-Michael; Attama, Anthony Amaechi

2016-01-01

The present study aimed to develop low-dose liquisolid tablets of two antimalarial drugs artemether–lumefantrine (AL) from a nanostructured lipid carrier (NLC) of lumefantrine (LUM) and estimate the potential of AL as an oral delivery system in malariogenic Wistar mice. LUM-NLCs were prepared by hot homogenization using Precirol® ATO 5/Transcutol® HP and tallow fat/Transcutol® HP optimized systems containing 3:1 ratios of the lipids, respectively, as the matrices. LUM-NLC characteristics, including morphology, particle size, zeta potential, encapsulation efficiency, yield, pH-dependent stability, and interaction studies, were investigated. Optimized LUM-NLCs were mixed with artemether powder and other dry ingredients and the resultant powder evaluated for micromeritics. Subsequent AL liquisolid tablets were tested for in vitro drug release and in vivo antiplasmodial activity in mice infected with Plasmodium berghei berghei (NK 65). Results showed that optimized LUM-NLC were stable, spherical, polydispersed but nanometric. Percentage yield and encapsulation efficiency were ~92% and 93% for Precirol® ATO 5/Transcutol® HP batch, then 81% and 95% for tallow fat/Transcutol® HP batch while LUM was amorphous in NLC matrix. In vitro AL release from liquisolid compacts revealed initial burst release and subsequent sustained release. Liquisolid tablet compacts formulated with Precirol® ATO 5/Transcutol® HP-AL4 achieved higher LUM release in simulated intestinal fluid (84.32%) than tallow fat/Transcutol® HP-BL3 (77.9%). Non-Fickian (anomalous) diffusion and super case II transport were the predominant mechanisms of drug release. Equal parasitemia reduction was observed for both batches of tablet compacts (~92%), superior to the reduction obtained with commercial antimalarial formulations: Coartem® tablets (86%) and chloroquine phosphate tablets (66%). No significant difference (P<0.05) in parasite reduction between double (4/24 mg/kg) and single (2/12 mg/kg) strength doses of AL compacts was observed. Our result highlights that AL could be formulated in much lower doses (4/24 mg/kg), for once-in-two days oral administration to improve patient compliance, which is currently not obtainable with conventional AL dosage forms. PMID:27932882

A secretory multifunctional serine protease, DegP of Plasmodium falciparum, plays an important role in thermo-oxidative stress, parasite growth and development.

PubMed

Sharma, Shweta; Jadli, Mohit; Singh, Anu; Arora, Kavita; Malhotra, Pawan

2014-03-01

Plasmodium falciparum heat shock proteins and proteases are known for their indispensable roles in parasite virulence and survival in the host cell. They neutralize various host-derived stress responses that are deleterious for parasite growth and invasion. We report identification and functional characterization of the first DegP from an apicomplexan (P. falciparum). To determine the molecular identity and functions of the parasite-encoded DegP, we complemented the Escherichia coli degP null mutant with a putative PfdegP gene, and the results showed that PfDegP complements the growth defect of the temperature sensitive DegP-deficient mutant and imparts resistance to non-permissive temperatures and oxidative stress. Molecular interaction studies showed that PfDegP exists as a complex with parasite-encoded heat shock protein 70, iron superoxide dismutase and enolase. DegP expression is significantly induced in parasite culture upon heat shock/oxidative stress. Our data suggest that the PfDegP protein may play a role in the growth and development of P. falciparum through its ability to confer protection against thermal/oxidative stress. Antibody against DegP showed anti-plasmodial activity against blood-stage parasites in vitro, suggesting that PfDegP and its associated complex may be a potential focus for new anti-malarial therapies. ●PfDegP physically interacts with PfHsp70 and PfEno by anti-bait co-immunoprecipitation (View interaction) ●PfDegP physically interacts with PfEno, PfSod, PfOat, PfHsp70, PfLDH and PfGpi by anti-bait co-immunoprecipitation (View interaction) ●PfHsp-70 and PfDegP co-localize by fluorescence microscopy (View interaction) ●PfDegP physically interacts with PfOat, PfHsp70, PfEno, PfSod, PfGpi and PfLDH by surface plasmon resonance (View interaction) ●PfEno and PfDegP co-localize by fluorescence microscopy (View interaction) ●PfDegP and PfHsp70 co-localize by co-sedimentation through density gradient (View interaction). © 2014 FEBS.

[Qualitative evaluation of employer requirements associated with occupational health and safety as good practice in small-scale enterprises].

PubMed

Kuroki, Naomi; Miyashita, Nana; Hino, Yoshiyuki; Kayashima, Kotaro; Fujino, Yoshihisa; Takada, Mikio; Nagata, Tomohisa; Yamataki, Hajime; Sakuragi, Sonoko; Kan, Hirohiko; Morita, Tetsuya; Ito, Akiyoshi; Mori, Koji

2009-09-01

The purpose of this study was to identify what motivates employers to promote good occupational health and safety practices in small-scale enterprises. Previous studies have shown that small-scale enterprises generally pay insufficient attention to issues of occupational health and safety. These findings were mainly derived from questionnaire based surveys. Nevertheless, some small-scale enterprises in which employers exercise good leadership do take a progressive approach to occupational health and safety. Although good practices can be identified in small-scale enterprises, it remains unclear what motivates employers in small-scale enterprises to actively implement occupational health and safety practices. We speculated that identifying employer motivations in promoting occupational health would help to spread good practices among small-scale enterprises. Using a qualitative approach based on the KJ methods, we interviewed ten employers who actively promote occupational health and safety in the workplace. The employers were asked to discuss their views of occupational health and safety in their own words. A semi-structured interview format was used, and transcripts were made of the interviews. Each transcript was independently coded by two or more researchers. These transcripts and codes were integrated and then the research group members discussed the heading titles and structural relationships between them according to the KJ method. Qualitative analysis revealed that all the employers expressed a strong interest in a "good company" and "good management". They emphasized four elements of "good management", namely "securing human resources", "trust of business partners", "social responsibility" and "employer's health condition itself", and considered that addressing occupational health and safety was essential to the achievement of these four elements. Consistent with previous findings, the results showed that implementation of occupational health and safety activities depended on "cost", "human resources", "time to perform", and "advisory organization". These results suggest that employer awareness of the relationship between good management and occupational health is essential to the implementation of occupational health and safety practices in small-scale enterprises.

Health-Related Quality of Life after Restorative Proctocolectomy: A Cross-Sectional Study.

PubMed

Helavirta, I; Hyöty, M; Oksanen, P; Huhtala, H; Haapamäki, J; Aitola, P

2018-05-01

Patients undergoing restorative proctocolectomy have often suffered from active ulcerative colitis which should be remembered when assessing quality of life after operation. The aim of this study was to explore health-related quality of life after restorative proctocolectomy in those with poor or good pouch function and to compare that to patients with active or inactive ulcerative colitis and to the general population. Altogether, 282 restorative proctocolectomy patients were investigated. The control group comprised 408 ulcerative colitis patients from the local register. Generic 15D and disease-specific inflammatory bowel disease questionnaire health-related quality of life instruments were used. Population-based data were available for 15D. Pouch function was evaluated with Öresland score and colitis activity with simple clinical colitis activity index. 15D results showed that patients with good pouch function had health-related quality of life similar to that of the general population. Health-related quality of life with inflammatory bowel disease questionnaire was equally good in patients with good pouch function (n = 131; 70%) and inactive colitis (n = 95; 63%), and equally impaired in patients with poor pouch function (n = 56; 30%) and active colitis (n = 18; 12%). The majority of patients had health-related quality of life comparable to that in general population. Most patients with active ulcerative colitis are likely to improve their health-related quality of life after successful surgery. These findings are important when informing colitis patients about life after surgery.

Antibacterial activity of crude methanolic extract and various fractions of Vitex agnus castus and Myrsine africana against clinical isolates of Methicillin Resistant Staphylococcus aureus.

PubMed

Ahmad, Bashir; Hafeez, Nabia; Ara, Gulshan; Azam, Sadiq; Bashir, Shumaila; Khan, Ibrar

2016-11-01

Staphylococcus aureus is a nosocomial pathogen that resides in the soft tissues causing many diseases. The current study was conducted to determine the prevalence of Methicillin Resistant S. aureus (MRSA) in ear discharge and pus of patients and antibacterial activity of crude methanolic extract (Cr. MeOH Ext.) and various fractions of M. Africana and V. agnus castus against clinical isolates of MRSA. A total of 40 samples were collected from ear, nose and throat (ENT) outpatient department and wards of Khyber Teaching Hospital (KTH), Peshawar. Out of 40 samples, 36 (90%) samples showed growth on Mannitol Salt Agar (MSA) media out of which 9(25%) were MRSA and the remaining 27(75%) were methicillin susceptible S. aureus (MSSA). A good antibacterial activity was observed for the Cr. MeOH Ext. (76.1%) and ethyl acetate (EtOAc) fraction of V. agnus castus against S11 (71.4%). The n-hexane fraction also showed good antibacterial effect (70%) against S 26 . The chloroform (CHCl3), butanol (BuOH) and aqueous fractions of M. africana showed good antibacterial activity against S 11 (71.4%), S32 (70%) and S 26 (75%), respectively. The above results revealed that the selected plants can be further utilized for isolation of the active ingredients as the crude extracts were found good for inhibition of MRSA.

The importance for daily occupations of perceiving good health: Perceptions among women with rheumatic diseases.

PubMed

Ottenvall Hammar, Isabelle; Håkansson, Carita

2013-03-01

The purpose was to describe and characterize what women with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) perceive as important in considering the performance of daily occupations to perceive good health. By using a phenomenographic research approach with semi-structured interviews with nine women between the ages of 42 and 65 the core category "Being able to be as active as possible in daily occupations" emerged. The women's repertoire of daily occupations had changed as the years had passed. To perceive good health the women expressed the importance of continuing to be active and to perform occupations as independently as possible despite their chronic rheumatic diseases. By adapting to their level of physical function and strength and by compensation with assistive devices, selecting adjusted environment, and by getting support from others, the women perceived good health. The results also suggested that training in different ways, medical treatment, and rheumatologic team care were related to increased performance of daily occupations and the perceptions of good health.

A Systematic Review of the Clinimetric Properties of Habitual Physical Activity Measures in Young Children with a Motor Disability

PubMed Central

Oftedal, Stina; Bell, Kristie L.; Mitchell, Louise E.; Davies, Peter S. W.; Ware, Robert S.; Boyd, Roslyn N.

2012-01-01

Aim. To identify and systematically review the clinimetric properties of habitual physical activity (HPA) measures in young children with a motor disability. Method. Five databases were searched for measures of HPA including: children aged <6.0 years with a neuromuscular disorder, physical activity defined as “bodily movement produced by skeletal muscles causing caloric expenditure”, reported HPA as duration, frequency, intensity, mode or energy expenditure, and evaluated clinimetric properties. The quality of papers was assessed using the COSMIN-checklist. A targeted search of identified measures found additional studies of typically developing young children (TDC). Results. Seven papers assessing four activity monitors met inclusion criteria. Four studies were of good methodological quality. The Minimod had good ability to measure continuous walking but the demonstrated poor ability to measure steps during free-living activities. The Intelligent Device for Energy Expenditure and Activity and Ambulatory Monitoring Pod showed poor ability to measure activity during both continuous walking and free-living activities. The StepWatch showed good ability to measure steps during continuous walking in TDC. Interpretation. Studies assessing the clinimetric properties of measures of HPA in this population are urgently needed to allow assessment of the relationship between HPA and health outcomes in this group. PMID:22927865

77 FR 16215 - Commission Information Collection Activities (FERC-716); Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-20

...: Title: FERC-716, Good Faith Request for Transmission Service and Response by Transmitting Utility Under... valid good faith request for transmission has been made under section 211 of the FPA. By developing the.... As a result, 18 CFR 2.20 identifies 12 components of a good faith estimate and 5 components of a...

Auctions to Reinforce Understanding

ERIC Educational Resources Information Center

Flores, Haynet Rivera

2018-01-01

An auction is a process of buying and selling goods or services by offering them up for bid, taking bids, and then selling each good or service to the highest bidder. Participants bid openly against one another; each bid must be higher than the previous bid. In the activity described rather than goods or services, English teachers sell sentences!…

76 FR 2123 - Agency Information Collection Activities; Announcement of Office of Management and Budget...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-12

...; Current Good Manufacturing Practice Quality System Regulation AGENCY: Food and Drug Administration, HHS... information entitled ``Current Good Manufacturing Practice Quality System Regulation'' has been approved by...

Perceived moral traits of others differentiate the neural activation that underlies inequity-aversion

PubMed Central

Nakatani, Hironori; Ogawa, Akitoshi; Suzuki, Chisato; Asamizuya, Takeshi; Ueno, Kenichi; Cheng, Kang; Okanoya, Kazuo

2017-01-01

We have a social preference to reduce inequity in the outcomes between oneself and others. Such a preference varies according to others. We performed functional magnetic resonance imaging during an economic game to investigate how the perceived moral traits of others modulate the neural activities that underlie inequity-aversion. The participants unilaterally allocated money to three partners (good, neutral, and bad). During presentation of the good and neutral partners, the anterior region of the rostral medial frontal cortex (arMFC) showed increased functional connectivity with the caudate head and the anterior insula, respectively. Following this, participants allocated more money to the good partner, and less to the bad partner, compared with the neutral partner. The caudate head and anterior insula showed greater activation during fair allocation to the good and unfair allocation to the neutral partners, respectively. However, these regions were silent during allocations to the bad partner. Therefore, the arMFC-caudate/insula circuit encompasses distinct neural processes that underlie inequity-aversion in monetary allocations that the different moral traits of others can modulate. PMID:28230155

Nanostructured titanium-silver coatings with good antibacterial activity and cytocompatibility fabricated by one-step magnetron sputtering

NASA Astrophysics Data System (ADS)

Bai, Long; Hang, Ruiqiang; Gao, Ang; Zhang, Xiangyu; Huang, Xiaobo; Wang, Yueyue; Tang, Bin; Zhao, Lingzhou; Chu, Paul K.

2015-11-01

Bacterial infection and loosing are serious complications for biomedical implants in the orthopedic, dental, and other biomedical fields and the ideal implants should combine good antibacterial ability and bioactivity. In this study, nanostructured titanium-silver (Ti-Ag) coatings with different Ag contents (1.2 to 21.6 at%) are prepared on Ti substrates by magnetron sputtering. As the Ag concentration is increased, the coatings change from having dense columnar crystals to sparse ones and eventually no columnar structure. The Ti-Ag coatings can effectively kill Staphylococcus aureus during the first few days and remain moderately antibacterial after immersion for 75 days. Compared to pure Ti, the Ti-Ag coatings show good cytocompatibility as indicated by good osteoblast adhesion, proliferation, intracellular total protein synthesis, and alkaline phosphatase (ALP) activity. In addition, cell spreading, collagen secretion, and extracellular matrix mineralization are promoted on the coatings with the proper Ag contents due to the nanostructured morphological features. Our results indicate that favorable antibacterial activity and osseointegration ability can be simultaneously achieved by regulating the Ag contents in Ti-Ag coatings.

Relationship between learning environment characteristics and academic engagement.

PubMed

Opdenakker, Marie-Christine; Minnaert, Alexander

2011-08-01

The relationship between learning environment characteristics and academic engagement of 777 Grade 6 children located in 41 learning environments was explored. Questionnaires were used to tap learning environment perceptions of children, their academic engagement, and their ethnic-cultural background. The basis of the learning environment questionnaire was the International System for Teacher Observation and Feedback (ISTOF). Factor analysis indicated three factors: the teacher as a helpful and good instructor (having good instructional skills, clear instruction), the teacher as promoter of active learning and differentiation, and the teacher as manager and organizer of classroom activities. Multilevel analysis indicated that about 12% of the differences in engagement between children was related to the learning environment. All the mentioned learning environment characteristics mattered, but the teacher as a helpful, good instructor was most important followed by the teacher as promoter of active learning and differentiation.

Biologically active perspective synthesis of heteroannulated 8-nitroquinolines with green chemistry approach.

PubMed

Arasakumar, Thangaraj; Mathusalini, Sadasivam; Gopalan, Subashini; Shyamsivappan, Selvaraj; Ata, Athar; Mohan, Palathurai Subramaniam

2017-04-01

A new class of pyrazolo[4,3-c]quinoline (5a-i, 7a-b) and pyrano[3,2-c]quinoline (9a-i) derivatives were designed and synthesized in moderate to good yields by microwave conditions. To enhance the yield of pyrano[3,2-c]quinoline derivatives, multicomponent one-pot synthesis has been developed. The synthesized compounds were identified by spectral and elemental analyses. Compounds 9a and 9i showed good antibacterial activity against Gram-positive and Gram-negative bacterial strains. All of the new compounds exhibited weak to moderate antioxidant activity, compound 9d exerted significant antioxidant power. The cytotoxicity of these compounds were also evaluated against MCF-7 (breast) and A549 (Lung) cancer cell lines. Most of the compounds displayed moderate to good cytotoxic activity against these cell lines. Compound 9i was found to be significantly active in this assay and also induced cell death by apoptosis. Molecular docking studies were carried out using EGFR inhibitor in order to determine the molecular interactions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis and evaluation of 7-substituted 4-aminoquinoline analogues for antimalarial activity.

PubMed

Hwang, Jong Yeon; Kawasuji, Takashi; Lowes, David J; Clark, Julie A; Connelly, Michele C; Zhu, Fangyi; Guiguemde, W Armand; Sigal, Martina S; Wilson, Emily B; Derisi, Joseph L; Guy, R Kiplin

2011-10-27

We previously reported that substituted 4-aminoquinolines with a phenyl ether substituent at the 7-position of the quinoline ring and the capability of intramolecular hydrogen bonding between the protonated amine on the side chain and a hydrogen bond acceptor on the amine's alkyl substituents exhibited potent antimalarial activity against the multidrug resistant strain P. falciparum W2. We employed a parallel synthetic method to generate diaryl ether, biaryl, and alkylaryl 4-aminoquinoline analogues in the background of a limited number of side chain variations that had previously afforded potent 4-aminoquinolines. All subsets were evaluated for their antimalarial activity against the chloroquine-sensitive strain 3D7 and the chloroquine-resistant K1 strain as well as for cytotoxicity against mammalian cell lines. While all three arrays showed good antimalarial activity, only the biaryl-containing subset showed consistently good potency against the drug-resistant K1 strain and good selectivity with regard to mammalian cytotoxicity. Overall, our data indicate that the biaryl-containing series contains promising candidates for further study.

JPRS Report, China, Qiushi (Seeking Truth), Number 1, 1 January 1990.

DTIC Science & Technology

1990-03-02

broad prospects and remain permanently in an invin- cible position. Correctly Understand the Market Situation, Actively Do a Good Job in Commodity...into consider- ation, the effective demand in the last two or three years was still greater than effective supply, and the market supply will remain...and actively increase supply, gradually achieving an overall balance between purchasing power and the supply of goods , the market will remain

[Synthesis, solubility, lipids-lowering and liver-protection activities of sulfonated formononetin].

PubMed

Wang, Qiu-ya; Meng, Qing-hua; Zhang, Zun-ting; Tian, Zhen-jun; Liu, Hui

2009-04-01

A water-soluble compound, sodium formononetin-3'-sulfonate with good lipid-lowering and liver-protection activities was synthesized. It was synthesized by sulfonation reaction, and its structure was characterized by IR, NMR and elemental analyses. The solubility of sodium formononetin-3'-sulfonate in water and n-octanol/water partition coefficient were determined by UV spectrophotometry. The lipid-lowering and liver-protection activities of sodium formononetin-3'-sulfonate were tested by using rat's high fat model induce by feeding with high fat food. The results showed that sodium formononetin-3'-sulfonate not only had favorable water, solubility but also had good lipid-lowering and liver-protection activities.

Biological activities and some physicochemical properties of sunflower honeys collected from the Thrace region of Turkey.

PubMed

Sari, Elif; Ayyildiz, Nusret

2012-12-01

Honey is a sweet food made by bees using nectar from flowers. Its quality depends on a number of factors, such as floral type, pH, moisture, free acidity, diastase activity, invert sugar and sucrose. The aim of the study is to examine the qualities of 50 sunflower honey (Helianthus annuus L.) collected from the Thrace region of Turkey, in terms of melissopalynological analysis, important chemical parameters and antioxidant activities . The total phenolic content of the honey samples was determined by the Folin-Ciocalteu method with spectrophotometry. The 1,2-diphenyl-2-picryl hydrazyl (DPPH) method was used to determine anti-radical activity and the phosphomolybdenum method was utilized for antioxidant activity. Correlations between the analysed parameters were found to be statistically significant (p < 0.05). The results obtained for physicochemical characteristics of sunflower honey indicate a good quality level, adequate processing, good maturity and freshness and that the sunflower honey samples studied proved to be good source of natural dietary antioxidants. This is the first report of the total phenolic content, antioxidant and antiradical activities of sunflower honeys collected from the Thrace region of Turkey.

Self-rated health among Greenlandic Inuit and Norwegian Sami adolescents: associated risk and protective correlates.

PubMed

Spein, Anna Rita; Pedersen, Cecilia Petrine; Silviken, Anne Cathrine; Melhus, Marita; Kvernmo, Siv Eli; Bjerregaard, Peter

2013-01-01

Self-rated health (SRH) and associated risk and protective correlates were investigated among two indigenous adolescent populations, Greenlandic Inuit and Norwegian Sami. Cross-sectional data were collected from "Well-being among Youth in Greenland" (WBYG) and "The Norwegian Arctic Adolescent Health Study" (NAAHS), conducted during 2003-2005 and comprising 10th and 11th graders, 378 Inuit and 350 Sami. SRH was assessed by one single item, using a 4-point and 5-point scale for NAAHS and WBYG, respectively. Logistic regressions were performed separately for each indigenous group using a dichotomous measure with "very good" (NAAHS) and "very good/good" (WBYG) as reference categories. We simultaneously controlled for various socio-demographics, risk correlates (drinking, smoking, violence and suicidal behaviour) and protective correlates (physical activity, well-being in school, number of close friends and adolescent-parent relationship). A majority of both Inuit (62%) and Sami (89%) youth reported "good" or "very good" SRH. The proportion of "poor/fair/not so good" SRH was three times higher among Inuit than Sami (38% vs. 11%, p≤0.001). Significantly more Inuit females than males reported "poor/fair" SRH (44% vs. 29%, p≤0.05), while no gender differences occurred among Sami (12% vs. 9%, p≤0.08). In both indigenous groups, suicidal thoughts (risk) and physical activity (protective) were associated with poor and good SRH, respectively. In accordance with other studies of indigenous adolescents, suicidal thoughts were strongly associated with poorer SRH among Sami and Inuit. The Inuit-Sami differences in SRH could partly be due to higher "risk" and lower "protective" correlates among Inuit than Sami. The positive impact of physical activity on SRH needs to be targeted in future intervention programs.

Good Exemplars of Natural Scene Categories Elicit Clearer Patterns than Bad Exemplars but Not Greater BOLD Activity

PubMed Central

Torralbo, Ana; Walther, Dirk B.; Chai, Barry; Caddigan, Eamon; Fei-Fei, Li; Beck, Diane M.

2013-01-01

Within the range of images that we might categorize as a “beach”, for example, some will be more representative of that category than others. Here we first confirmed that humans could categorize “good” exemplars better than “bad” exemplars of six scene categories and then explored whether brain regions previously implicated in natural scene categorization showed a similar sensitivity to how well an image exemplifies a category. In a behavioral experiment participants were more accurate and faster at categorizing good than bad exemplars of natural scenes. In an fMRI experiment participants passively viewed blocks of good or bad exemplars from the same six categories. A multi-voxel pattern classifier trained to discriminate among category blocks showed higher decoding accuracy for good than bad exemplars in the PPA, RSC and V1. This difference in decoding accuracy cannot be explained by differences in overall BOLD signal, as average BOLD activity was either equivalent or higher for bad than good scenes in these areas. These results provide further evidence that V1, RSC and the PPA not only contain information relevant for natural scene categorization, but their activity patterns mirror the fundamentally graded nature of human categories. Analysis of the image statistics of our good and bad exemplars shows that variability in low-level features and image structure is higher among bad than good exemplars. A simulation of our neuroimaging experiment suggests that such a difference in variance could account for the observed differences in decoding accuracy. These results are consistent with both low-level models of scene categorization and models that build categories around a prototype. PMID:23555588

Supporting your child with weight loss

MedlinePlus

... and reward your child when they make good food choices and participate in healthy activities . This will encourage ... so they can learn how to make good food choices. The best way to keep kids from eating ...

75 FR 10526 - In the Matter of Mr. Lawrence E. Grimm; Order Prohibiting Involvement in NRC-Licensed Activities

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-08

... rescind any of the above conditions upon demonstration by Mr. Grimm of good cause. V In accordance with 10... 20 days of its publication in the Federal Register. Where good cause is shown, consideration will be... statement of good cause for the extension. All documents filed in NRC adjudicatory proceedings, including a...

Why Physical Activity Is Important (for Girls)

MedlinePlus

... Home Fitness Why physical activity is important Why physical activity is important You may wonder if being physically ... you are to be around. That's partly because physical activity gets your brain to make "feel-good" chemicals ...

Malaria in the Renaissance: remedies from European herbals from the 16th and 17th century.

PubMed

Adams, Michael; Alther, Wandana; Kessler, Michael; Kluge, Martin; Hamburger, Matthias

2011-01-27

From antiquity up into the 20th century tertian and quartan malaria which are caused by the parasites Plasmodium vivax and Plasmodium malariae were widespread in Central Europe. Hundreds of different remedies against malaria can be found in herbals from the Renaissance. To document and discuss from a modern pharmacological viewpoint the old remedies described in eight 16th and 17th century herbals written in German. Eight of the most important herbals of the 16th and 17th century including Bock (1577), Fuchs (1543), Matthiolus (1590), Lonicerus (1560), Brunfels (1532), Zwinger (1696), and Tabernaemontanus (1591 and 1678) were searched for terms related to malaria, and documented plants and recipes described for its treatment. Additionally the overlapping of these remedies with those in De Materia Medica by the Greek physician Dioscorides was studied. Three hundred and fourteen taxa were identified in the herbals for this indication. Recent pharmacological data was found for just 5% of them. The influence of De Materia Medica was shown to be negligible with only 3.5% of the remedies in common. European Renaissance herbals may be a valuable source of information for the selection of plants for focussed antiplasmodial screening programmes, but have received only little scientific attention. Antimalarial remedies from these herbals must be viewed as independent sources of knowledge separate from Dioscorides' De Materia Medica. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Plasmodium evasion of mosquito immunity and global malaria transmission: The lock-and-key theory.

PubMed

Molina-Cruz, Alvaro; Canepa, Gaspar E; Kamath, Nitin; Pavlovic, Noelle V; Mu, Jianbing; Ramphul, Urvashi N; Ramirez, Jose Luis; Barillas-Mury, Carolina

2015-12-08

Plasmodium falciparum malaria originated in Africa and became global as humans migrated to other continents. During this journey, parasites encountered new mosquito species, some of them evolutionarily distant from African vectors. We have previously shown that the Pfs47 protein allows the parasite to evade the mosquito immune system of Anopheles gambiae mosquitoes. Here, we investigated the role of Pfs47-mediated immune evasion in the adaptation of P. falciparum to evolutionarily distant mosquito species. We found that P. falciparum isolates from Africa, Asia, or the Americas have low compatibility to malaria vectors from a different continent, an effect that is mediated by the mosquito immune system. We identified 42 different haplotypes of Pfs47 that have a strong geographic population structure and much lower haplotype diversity outside Africa. Replacement of the Pfs47 haplotypes in a P. falciparum isolate is sufficient to make it compatible to a different mosquito species. Those parasites that express a Pfs47 haplotype compatible with a given vector evade antiplasmodial immunity and survive. We propose that Pfs47-mediated immune evasion has been critical for the globalization of P. falciparum malaria as parasites adapted to new vector species. Our findings predict that this ongoing selective force by the mosquito immune system could influence the dispersal of Plasmodium genetic traits and point to Pfs47 as a potential target to block malaria transmission. A new model, the "lock-and-key theory" of P. falciparum globalization, is proposed, and its implications are discussed.

31 CFR 545.511 - Registration of nongovernmental organizations for humanitarian or religious activities.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., including the exportation of goods, software, technology or services to the territory of Afghanistan... applicable U.S. laws governing the exportation or reexportation of U.S.-origin goods, software, or technology...

31 CFR 538.521 - Registration of nongovernmental organizations for humanitarian or religious activities.

Code of Federal Regulations, 2010 CFR

2010-07-01

... organizations otherwise prohibited by this part, including the exportation of services, goods, software, or... reexportation of U.S.-origin goods, software, or technology (including technical data). See, e.g., the Export...

Discovery of an Isothiazole-Based Phenylpropanoic Acid GPR120 Agonist as a Development Candidate for Type 2 Diabetes.

PubMed

Zhang, Xuqing; Cai, Chaozhong; Sui, Zhihua; Macielag, Mark; Wang, Yuanping; Yan, Wen; Suckow, Arthur; Hua, Hong; Bell, Austin; Haug, Peter; Clapper, Wilma; Jenkinson, Celia; Gunnet, Joseph; Leonard, James; Murray, William V

2017-09-14

We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure-activity relationship studies led to the discovery of a potent GPR120 agonist 4x , which displayed good EC 50 values in both calcium and β-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.

Laughing: a demanding exercise for trunk muscles.

PubMed

Wagner, Heiko; Rehmes, Ulrich; Kohle, Daniel; Puta, Christian

2014-01-01

Social, psychological, and physiological studies have provided evidence indicating that laughter imposes an increased demand on trunk muscles. It was the aim of this study to quantify the activation of trunk muscles during laughter yoga in comparison with crunch and back lifting exercises regarding the mean trunk muscle activity. Muscular activity during laughter yoga exercises was measured by surface electromyography of 5 trunk muscles. The activation level of internal oblique muscle during laughter yoga is higher compared to the traditional exercises. The multifidus, erector spinae, and rectus abdominis muscles were nearly half activated during laughter yoga, while the activation of the external oblique muscle was comparable with the crunch and back lifting exercises. Our results indicate that laughter yoga has a positive effect on trunk muscle activation. Thus, laughter seems to be a good activator of trunk muscles, but further research is required whether laughter yoga is a good exercise to improve neuromuscular recruitment patterns for spine stability.

Translation, Cross-Cultural Adaptation, and Validation of the Activity Rating Scale for Disorders of the Knee

PubMed Central

Flosadottir, Vala; Roos, Ewa M.; Ageberg, Eva

2017-01-01

Background: The Activity Rating Scale (ARS) for disorders of the knee evaluates the level of activity by the frequency of participation in 4 separate activities with high demands on knee function, with a score ranging from 0 (none) to 16 (pivoting activities 4 times/wk). Purpose: To translate and cross-culturally adapt the ARS into Swedish and to assess measurement properties of the Swedish version of the ARS. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: The COSMIN guidelines were followed. Participants (N = 100 [55 women]; mean age, 27 years) who were undergoing rehabilitation for a knee injury completed the ARS twice for test-retest reliability. The Knee injury and Osteoarthritis Outcome Score (KOOS), Tegner Activity Scale (TAS), and modernized Saltin-Grimby Physical Activity Level Scale (SGPALS) were administered at baseline to validate the ARS. Construct validity and responsiveness of the ARS were evaluated by testing predefined hypotheses regarding correlations between the ARS, KOOS, TAS, and SGPALS. The Cronbach alpha, intraclass correlation coefficients, absolute reliability, standard error of measurement, smallest detectable change, and Spearman rank-order correlation coefficients were calculated. Results: The ARS showed good internal consistency (α ≈ 0.96), good test-retest reliability (intraclass correlation coefficient >0.9), and no systematic bias between measurements. The standard error of measurement was less than 2 points, and the smallest detectable change was less than 1 point at the group level and less than 5 points at the individual level. More than 75% of the hypotheses were confirmed, indicating good construct validity and good responsiveness of the ARS. Conclusion: The Swedish version of the ARS is valid, reliable, and responsive for evaluating the level of activity based on the frequency of participation in high-demand knee sports activities in young adults with a knee injury. PMID:28979920

Cultural activity participation and associations with self-perceived health, life-satisfaction and mental health: the Young HUNT Study, Norway.

PubMed

Hansen, Elisabeth; Sund, Erik; Skjei Knudtsen, Margunn; Krokstad, Steinar; Holmen, Turid Lingaas

2015-06-10

Leisure time activities and culture participation may have health effects and be important in pulic health promotion. More knowledge on how cultural activity participation may influence self-perceived health, life-satisfaction, self-esteem and mental health is needed. This article use data from the general population-based Norwegian HUNT Study, using the cross-sectional Young-HUNT3 (2006-08) Survey including 8200 adolescents. Data on cultural activity participation, self-perceived health, life-satisfaction, self-esteem, anxiety and depression were collected by self-reported questionnaires. Both attending meetings or training in an organisation or club, and attending sports events were positively associated with each of the health parameters good self-percieved health, good life-satisfaction, good self-esteem, and low anxiety and depression symptoms. We found differences according to gender and age (13-15 years versus 16-19 years old) for several culture activities, where girls aged 16-19 years seemed to benefit most from being culturally active. The extent of participation seemed to matter. Those who had frequent participation in cultural activities reported better health outcomes compared to inactive adolecents. The results from this study indicate that participation in cultural activities may be positively associated with health, life-satisfaction and self-esteem in adolescents and thus important in public health promotion. Possible sex and age differences should be taken into account.

Create a good learning environment and motivate active learning enthusiasm

NASA Astrophysics Data System (ADS)

Bi, Weihong; Fu, Guangwei; Fu, Xinghu; Zhang, Baojun; Liu, Qiang; Jin, Wa

2017-08-01

In view of the current poor learning initiative of undergraduates, the idea of creating a good learning environment and motivating active learning enthusiasm is proposed. In practice, the professional tutor is allocated and professional introduction course is opened for college freshman. It can promote communication between the professional teachers and students as early as possible, and guide students to know and devote the professional knowledge by the preconceived form. Practice results show that these solutions can improve the students interest in learning initiative, so that the active learning and self-learning has become a habit in the classroom.

Reliability and validity of a physical activity scale among urban pregnant women in eastern China.

PubMed

Jiang, Hong; He, Gengsheng; Li, Mu; Fan, Yanyan; Jiang, Hongyi; Bauman, Adrian; Qian, Xu

2015-03-01

This study aimed to determine the reliability and validity of the physical activity scale adapted from a Danish scale for assessing physical activity among urban pregnant women in eastern China. Participants recruited in an urban setting of eastern China were asked to complete the physical activity scale, the activity diary, and to wear a pedometer for the same 4 days, followed by repeating the activity scale for another 4 days within 2 weeks. A total of 109 pregnant women completed data recording. Good reliability of the physical activity scale was observed (intraclass correlation coefficient = .87). There was also a good comparability between the activity scale and the activity diary (Spearman's r = .75 for total energy expenditure). The agreement between the scale and pedometer reading was acceptable (Spearman's r = .45). The adapted physical activity scale is a reliable and reasonably accurate instrument for estimating physical activity among urban pregnant women in eastern China. © 2012 APJPH.

International physical activity questionnaire: reliability and validity of the Turkish version.

PubMed

Saglam, Melda; Arikan, Hulya; Savci, Sema; Inal-Ince, Deniz; Bosnak-Guclu, Meral; Karabulut, Erdem; Tokgozoglu, Lale

2010-08-01

Physical inactivity is a global problem which is related to many chronic health disorders. Physical activity scales which allow cross-cultural comparisons have been developed. The goal was to assess the reliability and validity of a Turkish version of the International Physical Activity Questionnaire (IPAQ). 1,097 university students (721 women, 376 men; ages 18-32) volunteered. Short and long forms of the IPAQ gave good agreement and comparable 1-wk. test-retest reliabilities. Caltrac accelerometer data were compared with IPAQ scores in 80 participants with good agreement for short and long forms. Turkish versions of the IPAQ short and long forms are reliable and valid in assessment of physical activity.

Synthesis and Biological Evaluation of Thiosemicarbazide Derivatives Endowed with High Activity toward Mycobacterium Bovis.

PubMed

Sardari, Soroush; Feizi, Samaneh; Rezayan, Ali Hossein; Azerang, Parisa; Shahcheragh, Seyyed Mohammad; Ghavami, Ghazaleh; Habibi, Azizollah

2017-01-01

Thiosemicarbazides are potent intermediates for the synthesis of pharmaceutical and bioactive materials and thus, they are used extensively in the field of medicinal chemistry. The imine bond (-N=CH-) in this compounds are useful in organic synthesis, in particular for the preparation of heterocycles and non-natural β-aminoacids. In this paper the synthesis of some new thiosemicarbazide derivatives by condensation reaction of various aldehydes or ketones with 4-phenylthiosemicarbazide or thiosemicarbazide is reported. This synthesis method has the advantages of high yields and good bioactivity. The structures of these compounds were confirmed by IR, mass, 1 H NMR, 13 C NMR, and single-crystal X-ray diffraction studies. All of these compounds were tested for their in-vitro anti-mycobacterial activity. The influence of the functional group and position of substituent on anti-bacterial activity of compounds is investigated too. The preliminary results indicated that all of the tested compounds showed good activity against the test organism. The compounds 11 and 30 showed the highest anti-tubercular activity (0.39 μg/mL). This synthesis method has the advantages of high yields and good bioactivity.

Predictors of good general health, well-being, and musculoskeletal disorders in Swedish dental hygienists.

PubMed

Ylipää, V; Arnetz, B B; Preber, H

1999-10-01

The aim of the present study was to examine how different personal, physical, and psychosocial work-associated factors are related to good general health, well-being, and musculoskeletal disorders in dental hygienists. A questionnaire was mailed to 575 dental hygienists who were randomly sampled from the Swedish Dental Hygienists' Association (86% responded). Data were analyzed with multiple-logistic regression models. The results showed that high clinical-practice fraction, active leisure, and high management support increased the odds for good general health, while work and family overload decreased the odds. Management support and mastery of work increased the odds for well-being, while work and family overload and high work efficiency decreased them. Scaling work increased the odds for general and work-related musculoskeletal disorders in all parts of the upper body and arms but not in the lower back. In the upper body, active leisure decreased the odds for general musculoskeletal disorders, while the odds for work-related musculoskeletal disorders increased from work and family overload and decreased from many weekly working hours. Many years in the profession increased the odds for general finger disorders. In conclusion, the results suggest that active leisure and several psychosocial work factors strongly influence good general health and well-being. Physical tasks influence musculoskeletal disorders more than active leisure and psychosocial work factors.

Performance of selective catalytic reduction of NO with NH3 over natural manganese ore catalysts at low temperature.

PubMed

Wang, Tao; Zhu, Chengzhu; Liu, Haibo; Xu, Yongpeng; Zou, Xuehua; Xu, Bin; Chen, Tianhu

2018-02-01

Natural manganese ore catalysts for selective catalytic reduction (SCR) of NO with NH 3 at low temperature in the presence and absence of SO 2 and H 2 O were systematically investigated. The physical and chemical properties of catalysts were characterized by X-ray diffraction, Brunauer-Emmett-Teller (BET) specific surface area, NH 3 temperature-programmed desorption (NH 3 -TPD) and NO-TPD methods. The results showed that natural manganese ore from Qingyang of Anhui Province had a good low-temperature activity and N 2 selectivity, and it could be a novel catalyst in terms of stability, good efficiency, good reusability and lower cost. The NO conversion exceeded 85% between 150°C and 300°C when the initial NO concentration was 1000 ppm. The activity was suppressed by adding H 2 O (10%) or SO 2 (100 or 200 ppm), respectively, and its activity could recover while the SO 2 supply is cut off. The simultaneous addition of H 2 O and SO 2 led to the increase of about 100% in SCR activity than bare addition of SO 2 . The formation of the amorphous MnO x , high concentration of lattice oxygen and surface-adsorbed oxygen groups and a lot of reducible species as well as adsorption of the reactants brought about excellent SCR performance and exhibited good SO 2 and H 2 O resistance.

Dose-response association between leisure time physical activity and work ability: Cross-sectional study among 3000 workers.

PubMed

Calatayud, Joaquin; Jakobsen, Markus D; Sundstrup, Emil; Casaña, Jose; Andersen, Lars L

2015-12-01

Regular physical activity is important for longevity and health, but knowledge about the optimal dose of physical activity for maintaining good work ability is unknown. This study investigates the association between intensity and duration of physical activity during leisure time and work ability in relation to physical demands of the job. From the 2010 round of the Danish Work Environment Cohort Study, currently employed wage earners with physically demanding work (n = 2952) replied to questions about work, lifestyle and health. Excellent (100 points), very good (75 points), good (50 points), fair (25 points) and poor (0 points) work ability in relation to the physical demands of the job was experienced by 18%, 40%, 30%, 10% and 2% of the respondents, respectively. General linear models that controlled for gender, age, physical and psychosocial work factors, lifestyle and chronic disease showed that the duration of high-intensity physical activity during leisure was positively associated with work ability, in a dose-response fashion (p < 0.001). Those performing ⩾ 5 hours of high-intensity physical activity per week had on average 8 points higher work ability than those not performing such activities. The duration of low-intensity leisure-time physical activity was not associated with work ability (p = 0.5668). The duration of high-intensity physical activity during leisure time is associated in a dose-response fashion with work ability, in workers with physically demanding jobs. © 2015 the Nordic Societies of Public Health.

Chemical constituents of essential oil of endemic Rhanterium suaveolens Desf. growing in Algerian Sahara with antibiofilm, antioxidant and anticholinesterase activities.

PubMed

Chemsa, Ahmed Elkhalifa; Erol, Ebru; Öztürk, Mehmet; Zellagui, Amar; Özgür, Ceylan; Gherraf, Noureddine; Duru, Mehmet Emin

2016-09-01

Twenty compounds were detected in the essential oil of Rhanterium suaveolens representing 98.01% of the total oil content. Perillaldehyde (45.79%), caryophyllene oxide (24.82%) and β-cadinol (5.61%) were identified as the main constituents. In β-carotene-linoleic acid assay, both the oil and the methanol extract exhibited good lipid peroxidation inhibition activity, with IC50 values of 17.97 ± 5.40 and 11.55 ± 3.39 μg/mL, respectively. In DPPH and CUPRAC assays, however, the methanol extract exhibited a good antioxidant activity. The highest antibiofilm activity has been found 50.30% against Staphylococcus epidermidis (MU 30) at 20 μg/mL for essential oil and 58.34% against Micrococcus luteus (NRRL B-4375) at 25 mg/mL concentration for methanol extract. The in vitro anticholinesterase activity of methanol extract showed a moderate acetylcholinesterase inhibitory (IC50 = 168.76 ± 0.62 μg/mL) and good butyrylcholinesterase inhibitory (IC50 = 54.79 ± 1.89 μg/mL) activities. The essential oil was inactive against both enzymes.

Comparison between the International Physical Activity Questionnaire and the American College of Sports Medicine/American Heart Association criteria to classify the physical activity profile in adults.

PubMed

de Moraes, Suzana Alves; Suzuki, Cláudio Shigueki; de Freitas, Isabel Cristina Martins

2013-01-01

the study aims to evaluate the reproducibility between the International Physical Activity Questionnaire and the American College of Sports Medicine/American Heart Association criteria to classify the physical activity profile in an adult population living in Ribeirão Preto, SP, Brazil. population-based cross-sectional study, including 930 adults of both genders. The reliability was evaluated by Kappa statistics, estimated according to socio-demographic strata. the kappa estimates showed good agreement between the two criteria in all strata. However, higher prevalence of "actives" was found by using the American College of Sports Medicine/American Heart Association. although the estimates have indicated good agreement, the findings suggest caution in choosing the criteria to classify physical activity profile mainly when "walking" is the main modality of physical activity.

Perceived health status and daily activity participation of older Malaysians.

PubMed

Ng, Sor Tho; Tengku-Aizan, Hamid; Tey, Nai Peng

2011-07-01

This article investigates the influence of perceived health status on the daily activity participation of older Malaysians. Data from the Survey on Perceptions of Needs and Problems of the Elderly, which was conducted in 1999, were used. The negative binomial regression results show that older persons with good perceived health status reported more varieties of daily activity participation, especially among the uneducated and those with below-average self-esteem. The multinomial logistic regression model suggests that older persons with good perceived health status tended to engage daily in paid work only or with leisure activities, whereas those perceived to have poor health were more likely to engage in leisure activities only or leisure and family role activities. Promotion of a healthy lifestyle at a younger age encourages every person to monitor and take responsibility for their own health, which is a necessary strategy to ensure active participation at an older age, and thus improve their well-being.

The concurrent validity of the Amharic version of Screening of Activity Limitation and Safety Awareness (SALSA) in persons affected by leprosy.

PubMed

Wijk, Ulrika; Brandsma, J Wim; Dahlström, Orjan; Björk, Mathilda

2013-03-01

Leprosy is endemic in many countries and results in activity limitations. There is a need for assessment tools to guide professionals in their evaluation and choice of intervention in order to improve conditions for leprosy-affected people. The purpose of our study was to evaluate the concurrent validity of the Amharic version of Screening of Activity Limitation and Safety Awareness (SALSA-am) scale with Amharic version of Disability of the Arm, Shoulder and Hand (DASH-am) questionnaire. Thirty-eight individuals with nerve damage due to leprosy completed the SALSA-am and DASH-am questionnaires. Spearman's rank correlation was used to determine relationships between SALSA and DASH scores. Specificity, sensitivity and accuracy were calculated. There was a good correlation 0.87 (P < 0.001) between SALSA-am and DASH-am scores. Sensitivity, specificity and accuracy were calculated with acceptable results. SALSA-am is considered a useful questionnaire for determining activity limitations in persons affected by leprosy, and showed good correlation with DASH-am. The concurrent validity was considered good.

Peroxidase-like catalytic activity of Mn(3+)-octabromo-tetrakis(4-sulfophenyl)porphine on linoleate hydroperoxide and its analytical application.

PubMed

Mifune, Masaki; Kamiguchi, Hidenori; Tai, Taka-Aki; Kuremoto, Seigo; Yamamoto, Makiko; Tsukamoto, Ikuko; Saito, Madoka; Kitamura, Youji; Saito, Yutaka

2007-01-15

To reveal an enzyme-like catalytic activity of metal-octabromo-tetrakis(sulfophenyl)porphines (M-OBPSs), their peroxidease-like catalytic activity on linoleate hydroperoxide (LOOH) were evaluated on the basis of dye-formation in the coloring reaction between N,N-diethylaniline and 4-aminoantipyrine that yields a quinoid-type dye. Among M-OBPSs tested, Mn(3+)-OBPS allowed to produce the largest amount of dye. The optimal conditions of the coloring reaction catalyzed by Mn(3+)-OBPS for the determination of LOOH were determined. A good linear calibration curve was obtained in the concentration range of 0.025-0.4mumole LOOH with good reproducibility (coefficient of variance=1.23%), suggesting that Mn(3+)-OBPS is a good artificial mimesis of the peroxidase for LOOH. In addition, Mn(3+)-OBPS was highly specific for LOOH even in the presence of cumene hydroxyperoxide or hydrogen peroxide. It was revealed that the peroxidase-like activity of Mn(3+)-OBTP is attributable to the redox cycle of Mn(3+)<-->Mn(4+).

Pyrazole derivatives as antitumor, anti-inflammatory and antibacterial agents.

PubMed

Liu, Jia-Jia; Zhao, Meng-Yue; Zhang, Xin; Zhao, Xin; Zhu, Hai-Liang

2013-11-01

Within the past years, many researches on the synthesis, structure-activity relationships (SAR), antitumor, antiinflammatory and anti-bacterial activities of the pyrazole derivatives have been reported. Several pyrazole derivatives possess important pharmacological activities and they have been proved useful materials in drug research. Pyrazole derivatives play an important role in antitumor agents because of their good inhibitory activity against BRAF(V600E), EGFR, telomerase, ROS Receptor Tyrosine Kinase and Aurora-A kinase. In addition, pyrazole derivatives also show good antiinflammatory and anti-bacterial activities. In this review, the bioactivities of the pyrazole derivatives mentioned above will be summarized in detail. We sincerely hope that increasing knowledge of the SAR and cellular processes underlying the bioactivity of pyrazole derivatives will be beneficial to the rational design of new generation of small molecule drugs.

Association of passive and active smoking with self-rated health and life satisfaction in Iranian children and adolescents: the CASPIAN IV study

PubMed Central

Heshmat, Ramin; Qorbani, Mostafa; Safiri, Saeid; Eslami-Shahr Babaki, Amir; Matin, Nassim; Motamed-Gorji, Nazgol; Motlagh, Mohammad-Esmaeil; Djalalinia, Shirin; Ardalan, Gelayol; Mansourian, Morteza; Asayesh, Hamid; Kelishadi, Roya

2017-01-01

Objective To assess the joint association of passive and active smoking with self-rated health and life satisfaction among Iranian children and adolescents. Methods Using a multistage random cluster sampling method, a representative sample of 14 880 school students were selected from urban and rural areas of 30 provinces of Iran. Data were gathered using a questionnaire, a weight scale and metre. Participants were classified into four groups based on their smoking patterns: ‘non-smoker’, ‘only active smoker’, ‘only passive smoker’ and ‘active and passive smoker’. Life satisfaction (LS) and self-rated health (SRH) were assessed by self-administered validated questionnaires based on the WHO-Global School-based student Health Survey (WHO-GSHS). Data were analysed using a t-test, χ2 test and multiple logistic regression. Results A total of 13 486 individuals (6640 girls and 6846 boys) out of 14 880 invited participated in the study (response rate 90.6%). LS and good SRH showed linearly negative associations with smoking status in both sexes. The proportions of LS and SRH categories were significantly different among all subsets of smoking status. Those classified as ‘non-smokers’ had the highest proportions of LS and good SRH, followed by ‘only passive smokers’ and ‘only active smokers’, while those with ‘active and passive smoking’ had the lowest proportions of LS and good SRH. In a multivariate model, students in the ‘active and passive smoking’ group had lower odds of LS (OR 0.43; 95% CI 0.32 to 0.57) and good SRH (OR 0.51; 95% CI 0.38 to 0.68) than those in the ‘non-smoker’ group. Students in the ‘only passive smoker’ group also had lower odds of LS (OR 0.75; 95% CI 0.67 to 0.83) and good SRH (OR 0.72; 95% CI 0.66 to 0.80) compared with the ‘non-smoker’ group. Conclusions Adolescents with different smoking habits and exposure patterns have poorer SRH and LS than non-smokers. Both active and passive smoking status could affect LS and SRH in adolescents. Therefore, smoking prevention strategies should be considered as a health priority in school health services for promoting psychological well-being in children and adolescents. PMID:28196944

An Economic Case against Vouchers: Why Local Public Schools Are a Local Public Good. Dartmouth Economics Department Working Paper.

ERIC Educational Resources Information Center

Fischel, William A.

This article offers an explanation and economic rationale for the failure of vouchers to be generally accepted by the public, suggesting that public schools are in fact a local public good. The reason economists fail to notice this is they look exclusively to the educational activity of the schools. Education is actually a private good, being both…

Baseline Air Quality Assessment of Goods Movement Activities before the Port of Charleston Expansion: A Community–University Collaborative

PubMed Central

Wilson, Sacoby M.; Tarver, Siobhan L.; Svendsen, Erik; Jiang, Chengsheng; Ogunsakin, Olalekan A.; Zhang, Hongmei; Campbell, Dayna; Fraser-Rahim, Herbert

2017-01-01

Abstract As the demand for goods continues to increase, a collective network of transportation systems is required to facilitate goods movement activities. This study examines air quality near the Port of Charleston before its expansion and briefly describes the establishment and structure of a community–university partnership used to monitor existing pollution. Particulate matter (PM) concentrations (PM2.5 and PM10) were measured using the Thermo Fisher Scientific Partisol 2000i-D Dichotomous Air Sampler, Thermo Scientific Dichotomous Sequential Air Sampler Partisol-Plus 2025-D, and Rupprecht & Patashnick TEOM Series 1400 Sampler at neighborhood (Union Heights, Rosemont, and Accabee) and reference (FAA2.5 and Jenkins Street) sites. Descriptive statistics were performed and an ANOVA (analysis of variance) was calculated to find the difference in overall mean 24-hour PM average concentrations in communities impacted by environmental injustice. PM2.5 (15.2 μg/m3) and PM10 (27.2 μg/m3) maximum concentrations were highest in neighborhoods such as Union Heights neighborhoods due to more goods movement activities. Nevertheless, there was no statistically significant difference in mean concentrations of PM2.5 and PM10 across neighborhood sites. In contrast, mean PM10 neighborhood concentrations were significantly lower than mean PM10 reference concentrations for Union Heights (p = 0.00), Accabee (p ≤ 0.0001), and Rosemont (p = 0.01). Although PM concentrations were lower than current National Ambient Air Quality Standards, this study demonstrated how community–university partners can work collectively to document baseline PM concentrations that will be used to examine changes in air quality after the port expansion brings additional goods movement activities to the area. PMID:29576842

Citrus pectin derived porous carbons as a superior adsorbent toward removal of methylene blue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Wenlin; Zhang, Lian Ying; Zhao, Xi Juan

An adsorbent, citrus pectin derived porous carbons with ultra-high adsorption capacity, rapid adsorption rate and good reusability toward removal of methylene blue, was synthesized by a facile zinc chloride activation approach in this study. The materials hold a great potential for treatment of dye wastewater. - Graphical abstract: Citrus pectin derived porous carbons with ultra-high adsorption capacity, rapid adsorption rate and good reusability toward methylene blue removal. - Highlights: • Citrus pectin derived porous carbons (CPPCs) were synthesized a facile zinc chloride activation approach. • CPPCs had abundant macro/meso/micropores for trapping MB molecules. • CPPCs exhibited ultrahigh adsorption capacity, rapidmore » adsorption rate and good reusability toward removal of MB.« less

Space activities - A review and a look ahead

NASA Technical Reports Server (NTRS)

Durrani, S. H.

1984-01-01

The paper reviews the progress made in manned and unmanned space programs during the last 25 years and names several major accomplishments. The ingredients of success are identified as good engineering, good technology, and good management of a very complex enterprise. An argument is made that the pace of progress will be governed not by technological advances, which can be very rapid, but rather by future institutional arrangements, which are much slower to evolve. It is predicted that the most likely space activities for the next 20 years will be those relating to space commercialization, and several examples are cited. A hope is expressed that policy makers and entrepreneurs will match the spirit of adventure and risk-taking exhibited by engineers in exploring uncharted territory.

Neural responses to taxation and voluntary giving reveal motives for charitable donations.

PubMed

Harbaugh, William T; Mayr, Ulrich; Burghart, Daniel R

2007-06-15

Civil societies function because people pay taxes and make charitable contributions to provide public goods. One possible motive for charitable contributions, called "pure altruism," is satisfied by increases in the public good no matter the source or intent. Another possible motive, "warm glow," is only fulfilled by an individual's own voluntary donations. Consistent with pure altruism, we find that even mandatory, tax-like transfers to a charity elicit neural activity in areas linked to reward processing. Moreover, neural responses to the charity's financial gains predict voluntary giving. However, consistent with warm glow, neural activity further increases when people make transfers voluntarily. Both pure altruism and warm-glow motives appear to determine the hedonic consequences of financial transfers to the public good.

Developing Science Communication in Africa: Undergraduate and Graduate Students should be Trained and Actively Involved in Outreach Activity Development and Implementation.

PubMed

Karikari, Thomas K; Yawson, Nat Ato; Quansah, Emmanuel

2016-01-01

Despite recent improvements in scientific research output from Africa, public understanding of science in many parts of the continent remains low. Science communication there is faced with challenges such as (i) lack of interest among some scientists, (ii) low availability of training programs for scientists, (iii) low literacy rates among the public, and (iv) multiplicity of languages. To address these challenges, new ways of training and motivating scientists to dialogue with non-scientists are essential. Developing communication skills early in researchers' scientific career would be a good way to enhance their public engagement abilities. Therefore, a potentially effective means to develop science communication in Africa would be to actively involve trainee scientists (i.e., undergraduate and graduate students) in outreach activity development and delivery. These students are often enthusiastic about science, eager to develop their teaching and communication skills, and can be good mentors to younger students. Involving them in all aspects of outreach activity is, therefore, likely to be a productive implementation strategy. However, science communication training specifically for students and the involvement of these students in outreach activity design and delivery are lacking in Africa. Here, we argue that improving the training and involvement of budding scientists in science communication activities would be a good way to bridge the wide gap between scientists and the African public.

Probiotic Properties of Lactobacillus fermentum Strains Isolated from Human Oral Samples and Description of their Antibacterial Activity.

PubMed

Fuochi, Virginia; Volti, Giovanni Li; Furneri, Pio M

2017-01-01

Gram positive bacteria produce peptides, defined bacteriocins which exhibit good antibacterial activity. We evaluated the ability of L. fermentum to produce bacteriocins having therefore, good probiotic features and finally, be safe towards microglial cells. Eight wild strains, identified using molecular techniques, were investigated for the evaluation of resistance to bile salts, low pH, H2O2 production, biofilm formation, antibacterial activity and safety on microglia cells (BV2). The determination of the susceptibility/resistance profile showed that the strains are sensitive to the antibiotics tested. All strains showed a good tolerability to extremely low pH as well as resisting in presence of bile salts. In addition, the strains showed excellent activity against pathogens and one of them (LAC 42) showed activity also against Pseudomonas aeruginosa and Klebsiella pneumoniae. Finally, LAC 42 and its active compound did not change microglia cell viability following 24h exposure. Our data on this antibacterial molecule suggest that it is a compound with low molecular weight and with highly hydrophilic component. These results describe the characteristics of Lactobacillus strains and provide evidences for their possible use as new potential probiotic. In addition, other studies are now warranted to exploit the antibacterial activity of the supernatant LAC 42 and for its complete chemical characterization. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The association between physical activity, cardiorespiratory fitness and self-rated health.

PubMed

Eriksen, Louise; Curtis, Tine; Grønbæk, Morten; Helge, Jørn W; Tolstrup, Janne S

2013-12-01

To investigate the joint association between self-reported physical activity as well as cardiorespiratory fitness and self-rated health among healthy women and men. Data from 10,416 participants in The Danish Health Examination Survey 2007-2008 which took part in 13 Danish municipalities were analyzed. Leisure time physical activity level and self-rated health were based on self-reported questionnaire data. Optimal self-rated health was defined as "very good" or "good" self-rated health. Cardiorespiratory fitness (mL O2·min(-1)·kg(-1)) was estimated from maximal power output in a maximal cycle exercise test. A strong dose-response relation between cardiorespiratory fitness and self-rated health as well as between physical activity level and self-rated health among both women and men was found. Within categories of physical activity, odds ratios for optimal self-rated health increased with increasing categories of cardiorespiratory fitness, and vice versa. Hence, participants who were moderately/vigorously physically active and had a high cardiorespiratory fitness had the highest odds ratio for optimal self-rated health compared with sedentary participants with low cardiorespiratory fitness (odds ratio=12.2, 95% confidence interval: 9.3-16.1). Although reluctant to conclude on causality, this study suggests that an active lifestyle as well as good cardiorespiratory fitness probably increase self-rated health. © 2013.

Activation of structural carbon fibres for potential applications in multifunctional structural supercapacitors.

PubMed

Qian, Hui; Diao, Hele; Shirshova, Natasha; Greenhalgh, Emile S; Steinke, Joachim G H; Shaffer, Milo S P; Bismarck, Alexander

2013-04-01

The feasibility of modifying conventional structural carbon fibres via activation has been studied to create fibres, which can be used simultaneously as electrode and reinforcement in structural composite supercapacitors. Both physical and chemical activation, including using steam, carbon dioxide, acid and potassium hydroxide, were conducted and the resulting fibre properties compared. It was proven that the chemical activation using potassium hydroxide is an effective method to prepare activated structural carbon fibres that possess both good electrochemical and mechanical properties. The optimal activation conditions, such as the loading of activating agent and the burn-off of carbon fibres, was identified and delivered a 100-fold increase in specific surface area and 50-fold improvement in specific electrochemical capacitance without any degradation of the fibre mechanical properties. The activation process was successfully scaled-up, showing good uniformity and reproducibility. These activated structural carbon fibres are promising candidates as reinforcement/electrodes for multifunctional structural energy storage devices. Copyright © 2012 Elsevier Inc. All rights reserved.

Neural correlates of self-deception and impression-management.

PubMed

Farrow, Tom F D; Burgess, Jenny; Wilkinson, Iain D; Hunter, Michael D

2015-01-01

Self-deception and impression-management comprise two types of deceptive, but generally socially acceptable behaviours, which are common in everyday life as well as being present in a number of psychiatric disorders. We sought to establish and dissociate the 'normal' brain substrates of self-deception and impression-management. Twenty healthy participants underwent fMRI scanning at 3T whilst completing the 'Balanced Inventory of Desirable Responding' test under two conditions: 'fake good', giving the most desirable impression possible and 'fake bad' giving an undesirable impression. Impression-management scores were more malleable to manipulation via 'faking' than self-deception scores. Response times to self-deception questions and 'fake bad' instructions were significantly longer than to impression-management questions and 'fake good' instructions respectively. Self-deception and impression-management manipulation and 'faking bad' were associated with activation of medial prefrontal cortex (mPFC) and left ventrolateral prefrontal cortex (vlPFC). Impression-management manipulation was additionally associated with activation of left dorsolateral prefrontal cortex and left posterior middle temporal gyrus. 'Faking bad' was additionally associated with activation of right vlPFC, left temporo-parietal junction and right cerebellum. There were no supra-threshold activations associated with 'faking good'. Our neuroimaging data suggest that manipulating self-deception and impression-management and more specifically 'faking bad' engages a common network comprising mPFC and left vlPFC. Shorter response times and lack of dissociable neural activations suggests that 'faking good', particularly when it comes to impression-management, may be our most practiced 'default' mode. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sulfated polysaccharides with antioxidant and anticoagulant activity from the sea cucumber Holothuria fuscogliva

NASA Astrophysics Data System (ADS)

Li, Rongfeng; Yu, Huahua; Yue, Yang; Liu, Song; Xing, Rong'e.; Chen, Xiaolin; Li, Pengcheng

2017-07-01

Sea cucumber is a traditional nutritional food and medicinal resource with many bioactive components in China. Holothuria fuscogliva is a big sea cucumber with a rich of bioactive polysaccharides. To investigate the bioactivities of the polysaccharides from sea cucumber H. fuscogliva, we prepared the sulfated polysaccharides (HfP) from sea cucumber H. fuscogliva using a protease hydrolysis method. Antioxidant activities of HfP were investigated, including hydroxyl radical scavenging activity and superoxide radical scavenging activity. And, the anticoagulant activities of HfP were studied, including the activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT). The average molecular weight was 1 867.1 Da, with a sulfate content of 20.7%. In addition, the molar ratio of monosaccharide composition of HfP was Man: Rha: Glc A: Glc: Gal: Xyl: Fuc=0.083 6: 0.437: 0.134: 0:1.182: 0.748: 1. It had a strong antioxidant activity, the hydroxyl and superoxide radical scavenging activity EC50 of HfP was 3.74 and 0.037 mg/mL, respectively. It also showed a good anticoagulant activity in our study. The APTT of HfP was much higher than that of heparin sodium, and the PT and TT of HfP was close to that of heparin sodium at a low concentration. Therefore, HfP shows a good antioxidant and anticoagulant activity and it may become a potential candidate of the natural antioxidant and anticoagulant and will have a good application future in health product or medicine industry.

The Navy SEAL Physical Fitness Guide

DTIC Science & Technology

1997-08-01

chafing. Thermal protection is not as good with the neck exposed . A good hood preserves a great deal of the swimmer’s heat. " Gloves may have webbed...the arms and also for the fins to chafe. Get thin booties without soles for fin use and consider using some vaseline or aquaphor ointment for other...specific activity that is to follow. This type of warm-up should be performed prior to high-intensity activities (e.g., O-Course, power-lifting, “ burn

Silicon oxide based high capacity anode materials for lithium ion batteries

DOEpatents

Deng, Haixia; Han, Yongbong; Masarapu, Charan; Anguchamy, Yogesh Kumar; Lopez, Herman A.; Kumar, Sujeet

2017-03-21

Silicon oxide based materials, including composites with various electrical conductive compositions, are formulated into desirable anodes. The anodes can be effectively combined into lithium ion batteries with high capacity cathode materials. In some formulations, supplemental lithium can be used to stabilize cycling as well as to reduce effects of first cycle irreversible capacity loss. Batteries are described with surprisingly good cycling properties with good specific capacities with respect to both cathode active weights and anode active weights.

[Antibacterial activity of cefpodoxime against clinical isolates in 2000 and 2001].

PubMed

Abe, Tomomi; Fukuoka, Takashi; Sato, Yuki; Ito, Kazuyoshi; Sei, Masami

2002-12-01

As the post-marketing surveillance of cefpodoxime proxetil (Banan), MICs of cefpodoxime (CPDX, an active form of Banan) against 1090 clinical isolates of 22 species from 15 medical institutions all over Japan from June 2000 to March 2001 were measured using the broth microdilution method approved by the Japanese Society of Chemotherapy and compared with those of oral cephem antibacterials, cefaclor, cefdinir, cefditoren, and cefcapene. In this study, remarkable change in the activity of CPDX was observed in Streptococcus pneumoniae and Haemophilus influenzae compared with the susceptibility in the studies before Banan was launched. This cause is considered to be the increase in the incidence of the following resistant strains: penicillin-intermediate S. pneumoniae (47.3%), penicillin-resistant S. pneumoniae (PRSP, 15.1%), and beta-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae (24.0%), which were scarcely isolated in 1989 when Banan was launched. Other tested drugs also exhibited low activity against these resistant strains. However, CPDX showed comparatively good activity with MIC90 of 2 micrograms/mL against PRSP. Against methicillin-susceptible Staphylococcus spp., Streptococcus pyogenes, Streptococcus agalactiae, and Moraxella catarrhalis, CPDX also showed comparatively good activity with MIC90 of < or = 4 micrograms/mL, which was almost equal to that in the studies before its marketing. Against quinolones-resistant Neisseria gonorrhoeae, CPDX showed excellent activity with MIC90 of 0.5 microgram/mL. Against members of the family Enterobacteriaceae except for Citrobacter freundii, Enterobacter spp., Proteus vulgaris, and Morganella morganii, CPDX showed good activity. However, in Escherichia coli, Klebsiella spp. Proteus spp., and Providencia spp., there are some high-resistant strains to all tested drugs including CPDX. Against Peptostreptococcus spp., MIC90 of CPDX was 8 micrograms/mL and its MIC range was widely distributed from 0.03 to 32 micrograms/mL, which were similar to those in the studies before its marketing. In this study, CPDX showed the decrease in the activity against several species as did other drugs tested, but against most of species tested, CPDX maintained good activity. Furthermore, it is necessary to pay much attention to the trend of resistant strains.

Electroplating on titanium alloy

NASA Technical Reports Server (NTRS)

Lowery, J. R.

1971-01-01

Activation process forms adherent electrodeposits of copper, nickel, and chromium on titanium alloy. Good adhesion of electroplated deposits is obtained by using acetic-hydrofluoric acid anodic activation process.

Delafloxacin: design, development and potential place in therapy.

PubMed

Candel, Francisco Javier; Peñuelas, Marina

2017-01-01

Delafloxacin (DLX) is a new fluoroquinolone pending approval, which has shown a good in vitro and in vivo activity against major pathogens associated with skin and soft tissue infections and community-acquired respiratory tract infections. DLX also shows good activity against a broad spectrum of microorganisms, including those resistant to other fluoroquinolones, as methicillin-resistant Staphylococcus aureus . Its pharmacokinetic properties and excellent activity in acidic environments make DLX an alternative in the treatment of these and other infections. In this manuscript, a detailed analysis of this new fluoroquinolone is performed, from its chemical structure to its in vivo activity in recently published clinical trials. Its possible place in the current antimicrobial outlook and in other infectious models is also discussed.

Delafloxacin: design, development and potential place in therapy

PubMed Central

Candel, Francisco Javier; Peñuelas, Marina

2017-01-01

Delafloxacin (DLX) is a new fluoroquinolone pending approval, which has shown a good in vitro and in vivo activity against major pathogens associated with skin and soft tissue infections and community-acquired respiratory tract infections. DLX also shows good activity against a broad spectrum of microorganisms, including those resistant to other fluoroquinolones, as methicillin-resistant Staphylococcus aureus. Its pharmacokinetic properties and excellent activity in acidic environments make DLX an alternative in the treatment of these and other infections. In this manuscript, a detailed analysis of this new fluoroquinolone is performed, from its chemical structure to its in vivo activity in recently published clinical trials. Its possible place in the current antimicrobial outlook and in other infectious models is also discussed. PMID:28356714

Preliminary antifungal activity assay of selected chlorine-containing derivatives of xanthone and phenoxyethyl amines.

PubMed

Klesiewicz, Karolina; Żelaszczyk, Dorota; Trojanowska, Danuta; Bogusz, Bożena; Małek, Marianna; Waszkielewicz, Anna; Szkaradek, Natalia; Karczewska, Elżbieta; Marona, Henryk; Budak, Alicja

2018-06-20

The aim of this study was to preliminary evaluate antifungal activity diverse group of chlorine-containing xanthone and phenoxyethyl amine derivatives - and to select most promising compounds for further studies. The antifungal efficacy of 16 compounds was tested with qualitative and quantitative methods against both reference and clinical strains of dermatophytes, moulds and yeasts. The disc-diffusion method has demonstrated that from 16 tested compounds, 7 possess good antifungal activity against dermatophytes and/or moulds while none of them has shown good efficacy against yeasts or bacterial strains. The most active compounds (2, 4, 10, 11, 12, 15, 16) were tested quantitatively by broth dilution method to obtain MIC values. The MIC values against dermatophytes ranged from 8 to 64 μg/mL. Compound 2 was the most active one against dermatophytes (MIC 50 and MIC 90 were 8 μg/mL). The MIC values for moulds ranged from 16 to 256 μg/mL. Compound 4 was the most active one against moulds, with MIC 50 and MIC 90 values amounting to 32 μg/mL. Among the tested compounds, compound 4 (derivative of xanthone) was the most active one and expressed good antifungal efficacy against clinical strains of dermatophytes and moulds. However, another xanthone derivative (compound 2) was the most active and selective against dermatophytes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Synthesis and characterization of curcumin-sulfonamide hybrids: Biological evaluation and molecular docking studies

NASA Astrophysics Data System (ADS)

Banuppriya, Govindharasu; Sribalan, Rajendran; Padmini, Vediappen

2018-03-01

Curcumin-sulfonamide hybrids (4a-e) were synthesized and their in vitro antioxidant, anti-inflammatory and anticancer activities were studied. The synthesized compounds showed a very good potent activity towards antioxidant and anti-inflammatory studies rather than its parent as well as standard. These compounds have exhibited an excellent toxicity effect to the cancer cell lines such as A549 and AGS. The compounds 4a and 4c have showed good anticancer activity than curcumin. The molecular docking studies were also performed against various Epidermal Growth Factor Receptor (EGFR) enzymes. The DFT calculations were also done in order to support the docking results.

Phytochemical analysis, antimicrobial, antioxidant and urease inhibitory potential of Cyphostemma digitatum Lam.

PubMed

Khan, Rasool; Saif, Abdullah Qasem; Quradha, Mohammad Mansour; Ali, Jawad; Rauf, Abdur

2015-01-01

In this paper we report the antimicrobial, antiradical and urease inhibitory potential along with photochemical investigation of the crude extracts of Cyphostemma digitatum Lam. Phytochemical screening of both the crude (hot/cold) alcoholic and aqueous extracts of C. digitatum showed the presence of alkaloids, flavonoids, saponins, coumarins, steroids, terpenoids and tannins. The crude methanolic extract (hot/cold) exhibited good antioxidant activity, while the aqueous extract was a weak antioxidant. The crude methanolic extract was found to be more active against Bacillus subtilis, while both the extracts showed moderate antifungal potential, the methanolic crude extract showed good urease inhibitory activity compared with the aqueous crude extract.

Design, synthesis, antiviral activity and three-dimensional quantitative structure-activity relationship study of novel 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety.

PubMed

Gan, Xiuhai; Hu, Deyu; Li, Pei; Wu, Jian; Chen, Xuewen; Xue, Wei; Song, Baoan

2016-03-01

1,4-Pentadien-3-one and 1,3,4-oxadiazole derivatives possess good antiviral activities, and their substructure units are usually used in antiviral agent design. In order to discover novel molecules with high antiviral activities, a series of 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety were designed and synthesised. Bioassays showed that most of the title compounds exhibited good inhibitory activities against tobacco mosaic virus (TMV) in vivo. The compound 8f possessing the best protective activity against TMV had an EC50 value of 135.56 mg L(-1) , which was superior to that of ribavirin (435.99 mg L(-1) ). Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were used in three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of protective activities, with values of q(2) and r(2) for the CoMFA and CoMSIA models of 0.751 and 0.775 and 0.936 and 0.925 respectively. Compound 8k with higher protective activity (EC50 = 123.53 mg L(-1) ) according to bioassay was designed and synthesised on the basis of the 3D-QSAR models. Some of the title compounds displayed good antiviral activities. 3D-QSAR models revealed that the appropriate compact electron-withdrawing and hydrophobic group at the benzene ring could enhance antiviral activity. These results could provide important structural insights for the design of highly active 1,4-pentadien-3-one derivatives. © 2015 Society of Chemical Industry.

Are a Healthy Diet and Physical Activity Synergistically Associated with Cognitive Functioning in Older Adults?

PubMed

Nijholt, W; Jager-Wittenaar, H; Visser, M; van der Schans, C P; Hobbelen, J S M

2016-01-01

Previous research has demonstrated that being both physically active and adhering a healthy diet is associated with improved cognitive functioning; however, it remains unclear whether these factors act synergistically. We investigated the synergistic association of a healthy diet and being physically active with cognitive functioning. Cross-sectional study. Data from the Longitudinal Aging Study Amsterdam (LASA) were used. We analyzed data from 2,165 community dwelling adults who were aged 55-85 years, 56% of whom were female. Cognitive functioning was assessed by the Mini-Mental State Examination (MMSE), an MMSE score of >26 indicates good cognitive functioning. Physical activity was assessed by the LASA Physical Activity Questionnaire and was considered sufficient if the person engaged in moderately intense physical activity ≥ 20 min/day. A healthy diet score was based on the intake of fruit, vegetables and fish. Each of the food groups was assigned a score that ranged from 1 (well below the Dutch guideline for a healthy diet) to 4 (well above the Dutch guideline for a healthy diet), and the scores were aggregated to determine a healthy diet (healthy ≥ 9 points). Multiple logistic and linear regression analyses were used to examine the (synergistic) association among physical activity, a healthy diet and cognitive functioning. All analyses were adjusted for potential chronic diseases and lifestyle confounders. Of all of the participants, 25% were diagnosed with a cognitive impairment (MMSE ≤26), 80% were physically active and 41% had a healthy diet. Sixty three percent of the participants both adhered to a healthy diet and were physically active. Sufficient daily physical activity (OR=2.545 p<.001) and adherence to a healthy diet (OR=1.766 p=.002) were associated with good cognitive functioning. After adjusting for confounding factors, sufficient physical activity was not significantly related to cognitive functioning (p=.163); however adherence to a healthy diet remained significantly associated with good cognitive functioning (p=.017). No interaction among sufficient physical activity, healthy diet adherence and good cognitive functioning was observed (crude: p=.401, adjusted: p=.216). The results of this cross-sectional study indicate that adherence to a healthy diet is inde-pendently related to cognitive functioning. Being physically active does not modify this association. Furthermore, these two lifestyle factors do not synergistically relate to cognitive functioning.

A Quantitative Model of Expert Transcription Typing

DTIC Science & Technology

1993-03-08

side of pure psychology, several researchers have argued that transcription typing is a particularly good activity for the study of human skilled...phenomenon with a quantitative METT prediction. The first, quick and dirty analysis gives a good prediction of the copy span, in fact, it is even...typing, it should be demonstrated that the mechanism of the model does not get in the way of good predictions. If situations occur where the entire

78 FR 76836 - Agency Information Collection Activities; Proposed Collection; Comment Request; Current Good...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-19

... Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements... of FDA's regulations regarding current good manufacturing practice (CGMP) for dietary supplements..., or Holding Operations for Dietary Supplements--21 CFR Part 111 (OMB Control Number 0910-0606...

75 FR 40840 - Agency Information Collection Activities; Proposed Collection; Comment Request; Current Good...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-14

... Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements... regulations regarding current good manufacturing practice (CGMP) for dietary supplements. DATES: Submit either... in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements--21 CFR Part 111...

Semiconducting compounds and devices incorporating same

DOEpatents

Marks, Tobin J; Facchetti, Antonio; Boudreault, Pierre-Luc; Miyauchi, Hiroyuki

2014-06-17

Disclosed are molecular and polymeric compounds having desirable properties as semiconducting materials. Such compounds can exhibit desirable electronic properties and possess processing advantages including solution-processability and/or good stability. Organic transistor and photovoltaic devices incorporating the present compounds as the active layer exhibit good device performance.

Divergent Angry Voices

ERIC Educational Resources Information Center

Brown, Paula; Finch, Kim; MacGregor, Cynthia; Watson, Robert

2012-01-01

In 2004, The U.S. Department of Education stated, "Great schools have great leaders" (p.1). Research supported their declaration as our nation actively pursued educational reform. School systems across the country searched for good school principals to lead, believing they were the "cornerstones of good schools" (DiPaola &…

Semiconducting compounds and devices incorporating same

DOEpatents

Marks, Tobin J.; Facchetti, Antonio; Boudreault, Pierre-Luc; Miyauchi, Hiroyuki

2016-01-19

Disclosed are molecular and polymeric compounds having desirable properties as semiconducting materials. Such compounds can exhibit desirable electronic properties and possess processing advantages including solution-processability and/or good stability. Organic transistor and photovoltaic devices incorporating the present compounds as the active layer exhibit good device performance.

Ecosystem Goods & Services and their Direct Linkages to Human Health & Well-Being

EPA Science Inventory

This presentation provides an overview of the SHC 2.61 Community-Based Final Ecosystem Goods and Services Project and other ecosystem services activities in the Office of Research and Development. Specifically, this presentation addressed a series of topics: Provide an overview ...

The diagnosis and treatment of donovanosis (granuloma inguinale).

PubMed Central

Richens, J

1991-01-01

Donovanosis is a predominantly tropical cause of genital ulcer occurring chiefly in small endemic foci in all continents except Europe. Diagnosis requires the careful collection, staining and examination of smears or biopsies of characteristic genital and, occasionally, extragenital lesions for demonstration of the pathognomonic Donovan bodies (Calymmatobacterium granulomatis) within histiocytes. Successful isolation of C. granulomatis has rarely proved feasible, the last report being in 1962. Donovanosis has a characteristic histopathological picture which occasionally simulates epithelioma. The antibiotics reported as showing good activity in donovanosis are those with good activity against gram negative bacilli and whose lipid solubility ensures good intracellular penetration. They include streptomycin, chloramphenicol, erythromycin, lincomycin, cotrimoxazole and the tetracyclines. More recently, good results have been reported with norfloxacin and thiamphenicol. The treatment of donovanosis in pregnant women and patients with AIDS poses special problems. Complications of donovanosis such as elephantiasis, stricture and pelvic abscess may require surgery. Contacts should be traced for examination but only treated if lesions are found. Images PMID:1774048

Weather during bloom affects pollination and yield of highbush blueberry.

PubMed

Tuell, Julianna K; Isaacs, Rufus

2010-06-01

Weather plays an important role in spring-blooming fruit crops due to the combined effects on bee activity, flower opening, pollen germination, and fertilization. To determine the effects of weather on highbush blueberry, Vaccinium corymbosum L., productivity, we monitored bee activity and compared fruit set, weight, and seed number in a field stocked with honey bees, Apis mellifera L., and common eastern bumble bees, Bombus impatiens (Cresson). Flowers were subjected to one of five treatments during bloom: enclosed, open, open during poor weather only, open during good weather only, or open during poor and good weather. Fewer bees of all types were observed foraging and fewer pollen foragers returned to colonies during poor weather than during good weather. There were also changes in foraging community composition: honey bees dominated during good weather, whereas bumble bees dominated during poor weather. Berries from flowers exposed only during poor weather had higher fruit set in 1 yr and higher berry weight in the other year compared with enclosed clusters. In both years, clusters exposed only during good weather had > 5 times as many mature seeds, weighed twice as much, and had double the fruit set of those not exposed. No significant increase over flowers exposed during good weather was observed when clusters were exposed during good and poor weather. Our results are discussed in terms of the role of weather during bloom on the contribution of bees adapted to foraging during cool conditions.

Implication of novel thiazolo-thiophene derivative (MCD-KV-10) for management of asthma.

PubMed

Patil, Dhiraj; Dash, Ranjeet Prasad; Thakur, Sandeep Kumar; Pandya, Amit N; Venkatesh, P; Vasu, Kamala K; Nivsarkar, Manish

2015-04-01

Asthma is multifaceted disease where many targets contribute towards its development and progression. Among these, adenosine receptor subtypes play a major role. MCD-KV-10, a novel thiazolo-thiophene was designed and evaluated pre-clinically for its implication in management of asthma. This compound showed good affinity and selectivity towards A(2A)/A3 adenosine receptor (AR) subtypes. Furthermore, MCD-KV-10 was evaluated for in vitro lipoxygenase inhibition activity; in vivo mast cell stabilization potential and in vivo anti-asthmatic activity was done in ovalbumin-induced airway inflammation model in guinea pigs. The compound showed good (>57%) inhibition of lipoxygenase enzyme and also effectively protected mast cell degranulation (>63%). The compound showed good anti-asthmatic activity as inferred from the in vivo studies. These results indicate that MCD-KV-10 has an inhibitory effect on airway inflammation. Though, we have identified a potential candidate for management of asthma, further mechanistic studies are needed.

Rational design of binder-free noble metal/metal oxide arrays with nanocauliflower structure for wide linear range nonenzymatic glucose detection

PubMed Central

Li, Zhenzhen; Xin, Yanmei; Zhang, Zhonghai; Wu, Hongjun; Wang, Peng

2015-01-01

One-dimensional nanocomposites of metal-oxide and noble metal were expected to present superior performance for nonenzymatic glucose detection due to its good conductivity and high catalytic activity inherited from noble metal and metal oxide respectively. As a proof of concept, we synthesized gold and copper oxide (Au/CuO) composite with unique one-dimensional nanocauliflowers structure. Due to the nature of the synthesis method, no any foreign binder was needed in keeping either Au or CuO in place. To the best of our knowledge, this is the first attempt in combining metal oxide and noble metal in a binder-free style for fabricating nonenzymatic glucose sensor. The Au/CuO nanocauliflowers with large electrochemical active surface and high electrolyte contact area would promise a wide linear range and high sensitive detection of glucose with good stability and reproducibility due to its good electrical conductivity of Au and high electrocatalytic activity of CuO. PMID:26068705

Validation of an Active Gear, Flexible Aircraft Take-off and Landing analysis (AGFATL)

NASA Technical Reports Server (NTRS)

Mcgehee, J. R.

1984-01-01

The results of an analytical investigation using a computer program for active gear, flexible aircraft take off and landing analysis (AGFATL) are compared with experimental data from shaker tests, drop tests, and simulated landing tests to validate the AGFATL computer program. Comparison of experimental and analytical responses for both passive and active gears indicates good agreement for shaker tests and drop tests. For the simulated landing tests, the passive and active gears were influenced by large strut binding friction forces. The inclusion of these undefined forces in the analytical simulations was difficult, and consequently only fair to good agreement was obtained. An assessment of the results from the investigation indicates that the AGFATL computer program is a valid tool for the study and initial design of series hydraulic active control landing gear systems.

WHO Expert Committee on specifications for pharmaceutical preparations.

PubMed

2010-01-01

The Expert Committee on Specifications for Pharmaceutical Preparations works towards clear, independent and practical standards and guidelines for the quality assurance of medicines. Standards are developed by the Committee through worldwide consultation and an international consensus-building process. The following new guidelines were adopted and recommended for use: good practices for pharmaceutical quality control laboratories; supplementary guidelines for active pharmaceutical ingredients; good manufacturing practices for pharmaceutical products containing hazardous substances; good manufacturing practices for sterile pharmaceutical products; good distribution practices for pharmaceutical products; guidelines on the requalification of prequalified dossiers: and guidelines for the preparation of a contract research organization master file.

What information strategy responding to social needs should be?

NASA Astrophysics Data System (ADS)

Fujii, Kunihiko

With the contemporary social phenomena that people think much of diversity of value, they are concerned with differentiation from others. Consumers' tendency to seek unique goods is common to all, giving impetus to makers' attitude that they try to produce varieties of goods but small amount for each. Consequently, life cycle of goods has become smaller than ever, and rapid and creative information gathering and utilization have become essential when makers produce goods responding to consumers' need. The author discusses how information strategy should be worked in the comprehensive business activities, and how information should be located as the powerful management resource.

Acetone leaf extracts of some South African trees with high activity against Escherichia coli also have good antimycobacterial activity and selectivity index.

PubMed

Elisha, Ishaku L; Botha, Francien S; Madikizela, Balungile; McGaw, Lyndy J; Eloff, Jacobus N

2017-06-19

Tuberculosis is a world-wide problem affecting humans and animals. There is increasing development of resistance of the pathogens to current antimycobacterial agents. Many authors have investigated activities of extracts and isolated compounds from plants. The traditional uses of plants have frequently been the criterion to select plants investigated. In this contribution, we investigate whether plant extracts with very good activity against Escherichia coli may also be active against mycobacteria. The antimycobacterial activity of eight South African tree leaf extracts with high activity against Escherichia coli were determined in vitro against Mycobacterium smegmatis, M. fortuitum and M. aurum, using a serial microdilution method. The cellular cytotoxicity was also determined by the MTT assay using Vero monkey kidney cells. The selectivity index was determined by dividing the cytotoxicity of extracts by MIC. The antimycobacterial activity of the extracts ranged from 0.02 to 2.5 mg/ml. Mycobacterium smegmatis was more sensitive to the extracts (Average MIC = 0.96 mg/ml) and Mycobacterium aurum was comparatively resistant (Average MIC = 2.04 mg/ml). The extracts of Cremaspora triflora had strong antimycobacterial activity with a MIC of 0.05 mg/ml that compared reasonably well with that of streptomycin (0.01 mg/ml) and rifampicin (0.03 mg/ml), p > 0.05. Cremaspora triflora had the best selectivity index of 2.87 against Mycobacterium fortuitum. The high activity of C. triflora extracts against the fast-growing mycobacteria and good cellular safety is promising. It may be interesting to investigate extracts against pathogenic M. tuberculosis, M. bovis and M. avium cultures and to isolate active antimycobacterial compounds.

77 FR 23732 - Agency Information Collection Activities; Announcement of Office of Management and Budget...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-20

...; Current Good Manufacturing Practices and Related Regulations for Blood and Blood Components; and Requirements for Donor Testing, Donor Notification, and ``Lookback'' AGENCY: Food and Drug Administration, HHS... information entitled ``Current Good Manufacturing Practices and Related Regulations for Blood and Blood...

29 CFR 784.17 - Basic coverage in general.

Code of Federal Regulations, 2010 CFR

2010-07-01

... employees who engage in specified activities concerned with interstate or foreign commerce. The employment of oppressive child labor in or about establishments producing goods for such commerce is also... commerce or in the production of goods for such commerce. The employer must observe the monetary standards...

25 CFR 143.2 - Purpose.

Code of Federal Regulations, 2010 CFR

2010-04-01

... AFFAIRS, DEPARTMENT OF THE INTERIOR FINANCIAL ACTIVITIES CHARGES FOR GOODS AND SERVICES PROVIDED TO NON... for the assessment, billing, and collection of charges for goods/services provided to non-Federal users. (b) The Assistant Secretary may sell or contract to sell to non-Federal users within, or in the...

A latent class multiple constraint multiple discrete-continuous extreme value model of time use and goods consumption.

DOT National Transportation Integrated Search

2016-06-01

This paper develops a microeconomic theory-based multiple discrete continuous choice model that considers: (a) that both goods consumption and time allocations (to work and non-work activities) enter separately as decision variables in the utility fu...

77 FR 47918 - Information Collection Activities (Released Rates)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-10

... decision in Released Rates of Motor Common Carriers of Household Goods, Docket No. RR 999 (Amendment No. 5... loss or damage that occurs during interstate household-good moves. See Safe, Accountable, Flexible... elects anything other than full-value protection. See Released Rates of Motor Common Carriers of...

78 FR 69648 - Civil Nuclear Trade Advisory Committee (CINTAC) Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-20

... DEPARTMENT OF COMMERCE International Trade Administration Civil Nuclear Trade Advisory Committee... nuclear goods and services in accordance with applicable U.S. laws and regulations, including advice on how U.S. civil nuclear goods and services export policies, programs, and activities will affect the U...

Effects of phonological contrast on auditory word discrimination in children with and without reading disability: A magnetoencephalography (MEG) study

PubMed Central

Wehner, Daniel T.; Ahlfors, Seppo P.; Mody, Maria

2007-01-01

Poor readers perform worse than their normal reading peers on a variety of speech perception tasks, which may be linked to their phonological processing abilities. The purpose of the study was to compare the brain activation patterns of normal and impaired readers on speech perception to better understand the phonological basis in reading disability. Whole-head magnetoencephalography (MEG) was recorded as good and poor readers, 7-13 years of age, performed an auditory word discrimination task. We used an auditory oddball paradigm in which the ‘deviant’ stimuli (/bat/, /kat/, /rat/) differed in the degree of phonological contrast (1 vs. 3 features) from a repeated standard word (/pat/). Both good and poor readers responded more slowly to deviants that were phonologically similar compared to deviants that were phonologically dissimilar to the standard word. Source analysis of the MEG data using Minimum Norm Estimation (MNE) showed that compared to good readers, poor readers had reduced left-hemisphere activation to the most demanding phonological condition reflecting their difficulties with phonological processing. Furthermore, unlike good readers, poor readers did not show differences in activation as a function of the degree of phonological contrast. These results are consistent with a phonological account of reading disability. PMID:17675109

Evaluation of antileishmanial, antibacterial and brine shrimp cytotoxic potential of crude methanolic extract of Herb Ocimum basilicum (Lamiacea).

PubMed

Khan, Imran; Ahmad, Kafeel; Khalil, Ali Talha; Khan, Jangrez; Khan, Yusra Ali; Saqib, Muhammad Shahab; Umar, Muhamad Naveed; Ahmad, Hilal

2015-06-01

To collect and screen for ethnopharmacological properties (antileishmanial, antibacterial and brine lethality assays) of medicinal plan Ocimum basilicum from Peshawar region (34.008 latitude and 71.57 altitudes). In the present study a general antileishmanial activity against Leishmania tropica strair was carried out. The antibacterial potential of the plant was performed against 06 gram positiv and 06 gram negative bacteria. Brine shrimp cyto- toxicity assay at different concentrations were investigated. The anti-promastigotes profile of the plant showed good antileishmanial activity exhibited LC50 value 21.67 µg/mL. The result for gram positive antibacterial activity revealed that the O. basilicum leaves extract possesses significant inhibitory activity at highest two concentrations ranging from 20.66 ± 0.31 to 31.86 ± 0.80 for Clostridium perfringens type C and Bacillus subtitilis, respectively, as compared to the gentamycin (27.36 ± 0.55 and 21.80 ± 0.72, respectively). For gram negative bacteria good activity was observed. A highest zone of inhibition was recorded for Pseudomonas aeroginosa (28.83 ± 0.28) at the highest concentration (10 mg/ mL). The LC50 value obtained for brine shrimp lethality assay was 91.56 µg/mL. The herb basil possesses effective cidal activities which make this plant a good candidate for the isolation of antiprotozoal and antibacterial compounds which may lead to the development of novel drug.

Go! Including Movement during Routines and Transitions

ERIC Educational Resources Information Center

Orlowski, Marietta A.; Hart, Aaron

2010-01-01

Good schools for children ages 5 to 8 provide multiple opportunities for physical activity throughout the school day. Ideally, physical education, recess, extracurricular activities, and classroom activities together help ensure that children meet the recommended 60 minutes a day of structured activity and 60 of unstructured. Additionally, brief…

Integration of Active Video Games in Extracurricular Activity at Schools

ERIC Educational Resources Information Center

Lee, Jung Eun; Huang, Charles; Pope, Zachary; Gao, Zan

2015-01-01

Active video games require players to be physically active. Dance Dance Revolution (DDR) is an interactive dancing game that requires fast-foot movement coordinated with energetic music and visuals. The Wii and Xbox Kinect games have also become good active video games for the promotion of physical activity participation. These games are much more…

Performing the good death: the medieval Ars moriendi and contemporary doctors.

PubMed

Thornton, K; Phillips, C B

2009-12-01

Death is inevitable, but dying well is not. Despite the role of medical professionals as overseers of dying in contemporary society, there is comparatively little discourse among doctors about the constituents of a good death. In the 15th century, by contrast, the Ars moriendi portrayed normative medieval ideas about good and bad deaths. At a time when dying could be viewed as a performed battle against damnation, the Ars moriendi codified a set of moral precepts that governed the expression of autonomy, relations between the dying and the living and orientation towards God. In these images, dying well is a moral activity that results from active decisions by the dying person to turn from earthly preoccupations to contemplation of, and submission to, the divine. It is likely in contemporary society that there is a range of understandings of the "good death". While attitudes to personal autonomy may differ, reflectiveness and dying at home in the presence of family (expressed in the Ars moriendi), remain part of many modern notions of the good death. We argue that medical institutions continue to construct death as a performed battle against physical debility, even when patients may have different views of their preferred deaths. The dialectic approach of the Ars moriendi may offer a way for contemporary doctors to reflect critically on the potential dissonance between their own approach to death and the variety of culturally valorised "good deaths".

Biological Activities of Aerial Parts Extracts of Euphorbia characias

PubMed Central

Pisano, Maria Barbara; Cosentino, Sofia; Viale, Silvia; Spanò, Delia; Corona, Angela; Esposito, Francesca; Tramontano, Enzo; Montoro, Paola; Tuberoso, Carlo Ignazio Giovanni; Medda, Rosaria; Pintus, Francesca

2016-01-01

The aim of the present study was to evaluate antioxidant, antimicrobial, anti-HIV, and cholinesterase inhibitory activities of aqueous and alcoholic extracts from leaves, stems, and flowers of Euphorbia characias. The extracts showed a high antioxidant activity and were a good source of total polyphenols and flavonoids. Ethanolic extracts from leaves and flowers displayed the highest inhibitory activity against acetylcholinesterase and butyrylcholinesterase, showing potential properties against Alzheimer's disease. Antimicrobial assay showed that leaves and flowers extracts were active against all Gram-positive bacteria tested. The ethanolic leaves extract appeared to have the strongest antibacterial activity against Bacillus cereus with MIC value of 312.5 μg/mL followed by Listeria monocytogenes and Staphylococcus aureus that also exhibited good sensitivity with MIC values of 1250 μg/mL. Moreover, all the extracts possessed anti-HIV activity. The ethanolic flower extract was the most potent inhibitor of HIV-1 RT DNA polymerase RNA-dependent and Ribonuclease H with IC50 values of 0.26 and 0.33 μg/mL, respectively. The LC-DAD metabolic profile showed that ethanolic leaves extract contains high levels of quercetin derivatives. This study suggests that Euphorbia characias extracts represent a good source of natural bioactive compounds which could be useful for pharmaceutical application as well as in food system for the prevention of the growth of food-borne bacteria and to extend the shelf-life of processed foods. PMID:27314007

Reported Prestroke Physical Activity Is Associated with Vascular Endothelial Growth Factor Expression and Good Outcomes after Stroke.

PubMed

López-Cancio, Elena; Ricciardi, Ana Clara; Sobrino, Tomás; Cortés, Jordi; de la Ossa, Natalia Pérez; Millán, Mónica; Hernández-Pérez, María; Gomis, Meritxell; Dorado, Laura; Muñoz-Narbona, Lucía; Campos, Francisco; Arenillas, Juan F; Dávalos, Antoni

2017-02-01

Physical activity (PhA) prior to stroke has been associated with good outcomes after the ischemic insult, but there is scarce data on the involved molecular mechanisms. We studied consecutive acute ischemic stroke patients admitted to a single tertiary stroke center. Prestroke PhA was evaluated with the International Physical Activity Questionnaire (metabolic equivalent of minutes/week). We studied several circulating angiogenic and neurogenic factors at different time points: vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor (G-CSF), and brain-derived neurotrophic factor (BDNF) at admission, day 7, and at 3 months. We considered good functional outcome at 3 months (modified Rankin scale  ≤ 2) as primary end point, and final infarct volume as secondary outcome. We studied 83 patients with at least 2 time point serum determinations (mean age 69.6 years, median National Institutes of Health Stroke Scale 17 at admission). Patients more physically active before stroke had a significantly higher increment of serum VEGF on the seventh day when compared to less active patients. This increment was an independent predictor of good functional outcome at 3 months and was associated with smaller infarct volume in multivariate analyses adjusted for relevant covariates. We did not find independent associations of G-CSF or BDNF levels neither with level of prestroke PhA nor with stroke outcomes. Although there are probably more molecular mechanisms by which PhA exerts its beneficial effects in stroke outcomes, our observation regarding the potential role of VEGF is plausible and in line with previous experimental studies. Further research in this field is needed. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Argument Based Science Inquiry (ABSI) Learning Model in Voltaic Cell Concept

NASA Astrophysics Data System (ADS)

Subarkah, C. Z.; Fadilah, A.; Aisyah, R.

2017-09-01

Voltaic Cell is a sub-concept of electrochemistry that is considered difficult to be comprehended by learners Voltaic Cell is a sub concept of electrochemistry that is considered difficult to be understood by learners so that impacts on student activity in learning process. Therefore the learning model Argument Based Science Inquiry (ABSI) will be applied to the concept of Voltaic cell. This research aims to describe students’ activities during learning process using ABSI model and to analyze students’ competency to solve ABSI-based worksheets (LK) of Voltaic Cell concept. The method used in this research was the “mix-method-quantitative-embedded” method with subjects of the study: 39 second-semester students of Chemistry Education study program. The student activity is quite good during ABSI learning. The students’ ability to complete worksheet (LK) for every average phase is good. In the phase of exploration of post instruction understanding, it is categorized very good, and in the phase of negotiation shape III: comparing science ideas to textbooks or other printed resources merely reach enough category. Thus, the ABSI learning has improved the student levels of activity and students’ competency to solve the ABSI-based worksheet (LK).

29 CFR 1620.4 - “Closely related” and “directly essential” activities.

Code of Federal Regulations, 2010 CFR

2010-07-01

... engaged in the production of goods for interstate or foreign commerce within the meaning of the FLSA even...; employees in the personnel, labor relations, employee benefits, safety and health, advertising, promotion... other facilities used in the production of goods for commerce, and such custodial and productive...

25 CFR 143.3 - Procedures.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false Procedures. 143.3 Section 143.3 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR FINANCIAL ACTIVITIES CHARGES FOR GOODS AND SERVICES PROVIDED TO NON-FEDERAL USERS § 143.3 Procedures. (a) All non-Federal users who receive the above listed goods/services...

25 CFR 143.1 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false Definitions. 143.1 Section 143.1 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR FINANCIAL ACTIVITIES CHARGES FOR GOODS AND SERVICES PROVIDED TO NON... costs incurred by the Government for the goods/services being provided. (d) Non-Federal users are...

The Business of Doing Good: A Creative Collaboration

ERIC Educational Resources Information Center

Matsuda, Matt; Williams, David S., II

2010-01-01

In this article, the authors report on a successful collaboration between academic and student services that resulted in a Rutgers University Byrne Seminar on social entrepreneurship. The course, entitled "The Business of Doing Good: Combining Business Practices with Social Activism," was designed to inspire the next generation of change makers,…

Consumer Education and the Human Services.

ERIC Educational Resources Information Center

Gartner, Alan

Consumer education has traditionally addressed activities related to the purchase of goods while the human services (e.g., health, education, and social welfare) have received far less attention. This condition stems from several factors, including the "doing good" attitude of human service providers and the role of government as the provider of…

78 FR 38193 - Continuation of the National Emergency With Respect to North Korea

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-25

..., including the procurement of luxury goods; and its illicit and deceptive activities in international markets... goods and currency, bulk cash smuggling, and narcotics trafficking, which destabilize the Korean... measures taken to deal with that national emergency, must continue in effect beyond June 26, 2013...

77 FR 37263 - Continuation of the National Emergency With Respect to North Korea

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-21

..., including the procurement of luxury goods; and its illicit and deceptive activities in international markets... goods and currency, bulk cash smuggling, and narcotics trafficking, which destabilize the Korean... measures taken to deal with that national emergency, must continue in effect beyond June 26, 2012...

Creating "Good Citizens" and Maintaining Religious Harmony in Singapore

ERIC Educational Resources Information Center

Tan, Charlene

2008-01-01

This article discusses how the concept of "good citizens" in Singapore is linked to the principle of harmony, characterised by collectivism and a strong interventionist government. The value of religious harmony is actively promoted by the Singapore government and supported by the religious leaders. This article argues that the principle…

Family Fitness Fun

Cancer.gov

Being active with your family can be a fun way to get everybody moving. All of you will get the health benefits that come from being active. Plus, you’ll be a positive role model, helping your children develop good habits for an active lifetime.

Direct Synthesis of Protoberberine Alkaloids by Rh-Catalyzed C-H Bond Activation as the Key Step.

PubMed

Jayakumar, Jayachandran; Cheng, Chien-Hong

2016-01-26

A one-pot reaction of substituted benzaldehydes with alkyne-amines by a Rh-catalyzed C-H activation and annulation to afford various natural and unnatural protoberberine alkaloids is reported. This reaction provides a convenient route for the generation of a compound library of protoberberine salts, which recently have attracted great attention because of their diverse biological activities. In addition, pyridinium salt derivatives can also be formed in good yields from α,β-unsaturated aldehydes and amino-alkynes. This reaction proceeds with excellent regioselectivity and good functional group compatibility under mild reaction conditions by using O2 as the oxidant. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Association of passive and active smoking with self-rated health and life satisfaction in Iranian children and adolescents: the CASPIAN IV study.

PubMed

Heshmat, Ramin; Qorbani, Mostafa; Safiri, Saeid; Eslami-Shahr Babaki, Amir; Matin, Nassim; Motamed-Gorji, Nazgol; Motlagh, Mohammad-Esmaeil; Djalalinia, Shirin; Ardalan, Gelayol; Mansourian, Morteza; Asayesh, Hamid; Kelishadi, Roya

2017-02-14

To assess the joint association of passive and active smoking with self-rated health and life satisfaction among Iranian children and adolescents. Using a multistage random cluster sampling method, a representative sample of 14 880 school students were selected from urban and rural areas of 30 provinces of Iran. Data were gathered using a questionnaire, a weight scale and metre. Participants were classified into four groups based on their smoking patterns: 'non-smoker', 'only active smoker', 'only passive smoker' and 'active and passive smoker'. Life satisfaction (LS) and self-rated health (SRH) were assessed by self-administered validated questionnaires based on the WHO-Global School-based student Health Survey (WHO-GSHS). Data were analysed using a t-test, χ 2 test and multiple logistic regression. A total of 13 486 individuals (6640 girls and 6846 boys) out of 14 880 invited participated in the study (response rate 90.6%). LS and good SRH showed linearly negative associations with smoking status in both sexes. The proportions of LS and SRH categories were significantly different among all subsets of smoking status. Those classified as 'non-smokers' had the highest proportions of LS and good SRH, followed by 'only passive smokers' and 'only active smokers', while those with 'active and passive smoking' had the lowest proportions of LS and good SRH. In a multivariate model, students in the 'active and passive smoking' group had lower odds of LS (OR 0.43; 95% CI 0.32 to 0.57) and good SRH (OR 0.51; 95% CI 0.38 to 0.68) than those in the 'non-smoker' group. Students in the 'only passive smoker' group also had lower odds of LS (OR 0.75; 95% CI 0.67 to 0.83) and good SRH (OR 0.72; 95% CI 0.66 to 0.80) compared with the 'non-smoker' group. Adolescents with different smoking habits and exposure patterns have poorer SRH and LS than non-smokers. Both active and passive smoking status could affect LS and SRH in adolescents. Therefore, smoking prevention strategies should be considered as a health priority in school health services for promoting psychological well-being in children and adolescents. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Dapson in heterocyclic chemistry, part VIII: synthesis, molecular docking and anticancer activity of some novel sulfonylbiscompounds carrying biologically active 1,3-dihydropyridine, chromene and chromenopyridine moieties.

PubMed

Al-Said, Mansour S; Ghorab, Mostafa M; Nissan, Yassin M

2012-07-02

Several new sulfonebiscompounds having a biologically active 1,2-dihydropyridine-2-one 3-19, acrylamide 20, chromene 21, 22 and chromenopyridine 23, 24 moieties were synthesized and evaluated as potential anticancer agents. The structures of the products were confirmed via elemental analyses and spectral data. The screening tests showed that many of the biscompounds obtained exhibited good anticancer activity against human breast cell line (MCF7) comparable to doxorubicin which was used as reference drug. Compounds 11, 17 and 24 showed IC50 values 35.40 μM, 29.86 μM and 30.99 μM, respectively. In order to elucidate the mechanism of action of the synthesized compounds as anticancer agents, docking on the active site of farnesyltransferase and arginine methyltransferase was also performed and good results were obtained.

Rhanterium epapposum Oliv. essential oil: Chemical composition and antimicrobial,insect-repellent and anticholinesterase activities

USDA-ARS?s Scientific Manuscript database

Essential oils from Rhanterium epapposum Oliv. (Asteraceae) was investigated for its repellent, antimicrobial and acetyl- and butyrylcholine esterase inhibitory activities. The oil showed good repellent activity while oils demonstrated weak in antimicrobial and cholinesterase inhibitions. Terpenoids...

32 CFR 700.1167 - Supremacist activity.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 5 2012-07-01 2012-07-01 false Supremacist activity. 700.1167 Section 700.1167 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY UNITED STATES NAVY REGULATIONS... organizations when such activities are detrimental to good order, discipline, or mission accomplishment. ...

32 CFR 700.1167 - Supremacist activity.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 5 2013-07-01 2013-07-01 false Supremacist activity. 700.1167 Section 700.1167 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY UNITED STATES NAVY REGULATIONS... organizations when such activities are detrimental to good order, discipline, or mission accomplishment. ...

32 CFR 700.1167 - Supremacist activity.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 5 2011-07-01 2011-07-01 false Supremacist activity. 700.1167 Section 700.1167 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY UNITED STATES NAVY REGULATIONS... organizations when such activities are detrimental to good order, discipline, or mission accomplishment. ...

32 CFR 700.1167 - Supremacist activity.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 5 2014-07-01 2014-07-01 false Supremacist activity. 700.1167 Section 700.1167 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY UNITED STATES NAVY REGULATIONS... organizations when such activities are detrimental to good order, discipline, or mission accomplishment. ...

32 CFR 700.1167 - Supremacist activity.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 5 2010-07-01 2010-07-01 false Supremacist activity. 700.1167 Section 700.1167 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY UNITED STATES NAVY REGULATIONS... organizations when such activities are detrimental to good order, discipline, or mission accomplishment. ...

Classroom Materials for Job-Related BSEP 2 Program

DTIC Science & Technology

1983-09-01

gathered D. gathered, combined, camoufl age 10. The greedy man was happy to take the money. A. greedy C. was *B. was happy D. take 11. The banana ...tastes good with peanut butter on it. A. tastes C. tastes good B. on D. banana III. Instructions: You are given a choice of two verbs in the following...previously o.- before. (The M16 had ALREADY been fired.) 162 peel Grammar Activity Sheet 36A Good Usage of English Name 6. ALL RIGHT - "ALRIGHT" ALL RIGHT

Marine-Natural-Product Development: First Discovery of Nortopsentin Alkaloids as Novel Antiviral, Anti-phytopathogenic-Fungus, and Insecticidal Agents.

PubMed

Ji, Xiaofei; Guo, Jincheng; Liu, Yuxiu; Lu, Aidang; Wang, Ziwen; Li, Yongqiang; Yang, Shaoxiang; Wang, Qingmin

2018-04-25

Nortopsentin alkaloids were found to have potent antiviral, anti-phytopathogenic-fungus, and insecticidal activities for the first time. Antiviral-activity tests revealed that these compounds were very sensitive to substituents, so a series of nortopsentin derivatives were designed, synthesized, and systematically evaluated for their antiviral activities against TMV, their fungicidal activities, and their insecticidal activities on the basis of a structural-diversity-derivation strategy. Compounds 2e (in vivo inactivation-, curative-, and protective-activity inhibitory rates of 50, 59, and 56%, respectively, at 500 μg/mL) and 2k (in vivo inactivation-, curative-, and protective-activity inhibitory rates of 60, 58, and 52%, respectively, at 500 μg/mL), with excellent antiviral activities and good physicochemical properties, emerged as new lead compounds for novel-antiviral-agent development. Further fungicidal-activity tests revealed that these alkaloids displayed broad-spectrum fungicidal activities. Compounds 2f, 2h, and 2j emerged as new lead compounds for antifungal-activity research. Additionally, all the compounds displayed good insecticidal activities against five kinds of insects, including Mythimna separate, Helicoverpa armigera, Ostrinia nubilalis, Plutella xylostella, and Culex pipiens pallens.

Determinants of sexual activity in four birth cohorts of Swedish 70-year-olds examined 1971-2001.

PubMed

Beckman, Nils; Waern, Margda; Östling, Svante; Sundh, Valter; Skoog, Ingmar

2014-02-01

Knowledge about determinants of sexual activity in older adults in the general population is limited. Human senescence has been delayed by a decade, and people are reaching old age in better health. The aim of this study was to investigate determinants of sexual activity in four birth cohorts of non-demented 70-year-olds examined in 1971-1977 and 1992-2001. The main outcome measure was sexual activity (defined as intercourse) during the past year. The study is based on cross-sectional data from four population samples of 70-year-olds from Gothenburg, Sweden (N = 1,407) systematically sampled from the Swedish population register. In the time periods 1971-1972 and 2000-2001, sexual activity among men increased from 47% to 66%, and in women from 12% to 34%. Sexual activity was related to positive attitude toward sexuality, sexual debut before age 20, having a very happy relationship, having a physically and mentally healthy partner, self-reported good global health, interviewer-rated good mental health, being married/cohabiting, satisfaction with sleep, and drinking alcohol more than three times a week. Having an older partner, diabetes mellitus, coronary heart disease, higher physical health-sum score, and depression were related to less sexual activity. Interaction effects for birth cohort, with stronger positive associations in 1971-1972, were found for positive attitude toward sexuality, strong desire at age 20-30, premarital sexuality, having a younger partner, self-reported good global health, interviewer-rated good global mental health, overweight, and satisfaction with sleep. Having an older partner and depression showed stronger negative associations in the 1970s. Physical health-sum score showed a stronger negative association in 1992-2001. We found that determinants of sexual activity in older people are numerous and varied, and change over time. It is thus important that health professionals and others take a holistic approach when dealing with sexual problems in older adults. Sexual aging should be part of health care and medical education. Clinicians should be trained to ask older patients about sexual concerns. © 2013 International Society for Sexual Medicine.

How to run a successful Journal

PubMed Central

Jawaid, Shaukat Ali; Jawaid, Masood

2017-01-01

Publishing and successfully running a good quality peer reviewed biomedical scientific journal is not an easy task. Some of the pre-requisites include a competent experienced editor supported by a team. Long term sustainability of a journal will depend on good quality manuscripts, active editorial board, good quality of reviewers, workable business model to ensure financial support, increased visibility which will ensure increased submissions, indexation in various important databases, online availability and easy to use website. This manuscript outlines the logistics and technical issues which need to be resolved before starting a new journal and ensuring sustainability of a good quality peer reviewed journal. PMID:29492089

Active Play: Exploring the Influences on Children's School Playground Activities

ERIC Educational Resources Information Center

Hyndman, Brendon; Benson, Amanda; Telford, Amanda

2016-01-01

Because children spend so much of their time in schools, their playgrounds offer a good setting for promoting active play in young lives. Teachers, instead of considering active play a taxing demand on their busy day, have begun to develop an informal curriculum for it. The authors review the research on children's active play and explores its…