Antiplasmodial Activity Of Compounds Research Articles

Steroids from Diplazium esculentum: Antiplasmodial activity and molecular docking studies to investigate their binding modes.

Diplazium esculentum is an edible fern commonly consumed by the local community in Malaysia either as food or medicine. Isolation work on the ethyl acetate extract of the stem of D. esculentum resulted in the purification of two steroids, subsequently identified as stigmasterol (compound 1) and ergosterol5,8-endoperoxide (compound 2). Upon further testing, compound 2 displayed strong inhibitory activity against the Plasmodium falciparum 3D7 (chloroquine-sensitive) strain, with an IC50 of 4.27±1.15 µM, while compound 1 was inactive. In silico data revealed that compound 2 showed good binding affinity to P. falciparum-Sarco endoplasmic reticulum calcium-dependent ATPase (PfATP6); however, compound 1 did not show an antiplasmodial effect due to the lack of a peroxide moiety in the chemical structure. Our data suggested that the antiplasmodial activity of compound 2 from D. esculentum might be due to the inhibition of PfATP6, which resulted in both in vitro and in silico inhibitory properties.

In Vitro Antiplasmodial, Heme Polymerization, and Cytotoxicity of Hydroxyxanthone Derivatives.

The previous study showed that xanthone had antiplasmodial activity. Xanthone, with additional hydroxyl groups, was synthesized to increase its antiplasmodial activity. One of the strategies to evaluate a compound that can be developed into an antimalarial drug is by testing its mechanism in inhibiting heme polymerization. In acidic condition, hematin can be polymerized to β-hematin in vitro, which is analog with hemozoin in Plasmodium. This study was conducted to evaluate the antiplasmodial activity of hydroxyxanthone derivative compounds on two strains of Plasmodium falciparum 3D-7 and FCR-3, to assess inhibition of heme polymerization activity and determine the selectivity of hydroxyxanthone derivative compounds. The antiplasmodial activity of each compound was tested on Plasmodium falciparum 3D-7 and FCR-3 with 72 hours incubation period, triplicated in three replications with the microscopic method. The compound that showed the best antiplasmodial activity underwent flow cytometry assay. Heme polymerization inhibition test was performed using the in vitro heme polymerization inhibition activity (HPIA) assay. The antiplasmodial activity and heme polymerization inhibition activity were expressed as the 50% inhibitory concentration (IC50). In vitro cytotoxicity was tested using the MTT assay method on Vero cell lines to determine its selectivity index. The results showed that among 5-hydroxyxanthone derivative compounds, the 1,6,8-trihydroxyxanthone had the best in vitro antiplasmodial activity on both 3D-7 and FCR-3 Plasmodium falciparum strains with IC50 values of 6.10 ± 2.01 and 6.76 ± 2.38 μM, respectively. The 1,6,8-trihydroxyxanthone showed inhibition activity of heme polymerization with IC50 value of 2.854 mM and showed the high selectivity with selectivity index of 502.2–556.54. In conclusion, among 5-hydroxyxanthone derivatives tested, the 1,6,8-trihydroxyxantone showed the best antiplasmodial activity and has heme polymerization inhibition activity and high selectivity.

In silico and in vivo anti-malarial investigation on 1-(heteroaryl)-2-((5-nitroheteroaryl)methylene) hydrazine derivatives

BackgroundResistance of Plasmodium falciparum against common anti-malarial drugs emphasizes the need of alternative and more effective drugs. Synthetic derivatives of 1-(heteroaryl)-2-((5-nitroheteroaryl)methylene) hydrazine have showed in vitro anti-plasmodial activities. The present study aimed to evaluate the molecular binding and anti-plasmodial activity of synthetic compounds in vivo.MethodsThe molecular docking was used to study the binding of compounds to haem and Plasmodium falciparum lactate dehydrogenase (PfLDH). Acute toxicity of the synthetic compounds was evaluated based on the modified up & down method. The anti-plasmodial activity of the compounds was conducted by the two standard tests of Peters’ and of Rane, using chloroquine-sensitive Plasmodium berghei in mice. Also, the toxicity to the internal organs of mice was evaluated on the seventh day after the treatment in addition to the histopathology of their liver. Compound 3 that showed high activity in the lowest dose was selected for further pharmacodynamic studies.ResultsAccording to the docking studies, the active site of PfLDH had at least four common residues, including Ala98, Ile54, Gly29, and Tyr97 to bind the compounds with the affinity, ranging from − 8.0 to − 8.4 kcal/mol. The binding mode of ligands to haem revealed an effective binding affinity, ranging from − 5.1 to − 5.5 kcal/mol. Compound 2 showed the highest % suppression of parasitaemia (99.09%) at the dose of 125 mg/kg/day in Peters’ test. Compound 3, with 79.42% suppression, was the best in Rane’s test at the lowest dose (31 mg/kg/day). Compound 3 was confirmed by the pharmacodynamic study to have faster initial parasite elimination in the lowest concentration. The histopathology of the livers of mice did not reveal any focal necrosis of hepatocytes in the studied compounds.ConclusionsThe docking studies verified Pf LDH inhibition and the inhibitory effect on the haemozoin formation for the studied compounds. Accordingly, some compounds may provide new avenues for the development of anti-malarial drugs without liver toxicity, although further studies are required to optimize their anti-plasmodial activity.

Halogenation as a Strategy to Improve Antiplasmodial Activity: A Report of New 3-Alkylpyridine Marine Alkaloid Analogs

Introduction: Due to the emergence of resistance to antimalarial drugs as well as the lack of vaccination for malaria, there is an urgent demand for the development of new antimalarial alternatives. Recently, our research group developed a new set of 3-alkylpyridine marine alkaloid analogs, of which a compound known as compound 5 was found to be inactive against Plasmodium falciparum.Methods: Herein, we report a successful halogenation strategy to improve the antiplasmodial activity of compound 5 through the replacement of a hydroxyl group by chlorine (compound 6) and fluorine (compound 7) atoms. Results: Compounds 6 and 7 showed improved antiplasmodial activities (IC50 = 7.2 and 8.3 µM, respectively) 20 times higher than that of their precursor, compound 5 (IC50 = 210.7 µM). Ultraviolet-visible titration experiments demonstrated that halogenation of compound 5 did not alter its ability to bind its target, hematin. Conclusion: Halogenation can enhance the antiplasmodial activity of a compound without altering its mechanism of action.

Melimoluccanin, A new isoprenylated quinolone alkaloid from the leaves of Melicope moluccana T.G. Hartley

A new quinolone alkaloid, melimoluccanin (1) along with two known alkaloids, leptanoine C (2) and 7-O-isoprenyl-γ-fagarin (3) were isolated from the leaves of Melicope moluccana T.G. Hartley. Structures all of compounds were elucidated using spectroscopic methods such as UV, IR, HRESIMS, 1D and 2D NMR. Compounds 1-3 were evaluated for their cytotoxicity against P-388 cells and for antimalaria activity using giemsa methods. The cytotoxic data of compounds 1-3 showed IC50 of 0.63; 5.85 and 2.09 μg/mL, respectively. The antiplasmodial activity of compound 1-3 showed IC50 value of 4.28; 2,28 and 0.18 μg/mL, respectively. Based on the data, it can be concluded that compound 1 has high activity against P-388 cells and compound 3 is potential as antimalaria.

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

Ethnopharmacological relevanceMalaria 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. Materials and methodsThe 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. ResultsA 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 50μg/mL) elicited by one of the dichloromethane root extracts. ConclusionOur 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.

Samvisterin, a new natural antiplasmodial betulin derivative from Uapaca paludosa (Euphorbiaceae)

Ethnopharmacological relevanceUapaca paludosa is used in African traditional medicine for the treatment of malaria. Materials and methodsA bioguided fractionation of U. paludosa trunk bark extracts was performed on the basis of their antiplasmodial activity against Plasmodium falciparum. ResultsA new natural betulin derivative named samvisterin (2) was isolated. In addition, 12 already known compounds were isolated from U. paludosa and tested against P. falciparum: squalene (1); lupeol (3), betulonic acid methyl ester (4), β-sitosterol (5), stigmasterol (6), betulin (7), betulinic acid (8), pentadecanoic acid (9), palmitic acid (10), margaric acid (11), stearic acid (12), methyl palmitate (13). With the exception of betulinic acid, all were isolated for the first time from U. paludosa. Their chemical structures were established on the basis of spectroscopic analysis. The antiplasmodial activity of compounds 1–8 was confirmed on the chloroquine-resistant strain of P. falciparum, FcM29-Cameroon, with IC50 values ranging from 0.7μg/ml (for 1) to 30μg/mL (for 3). The cytotoxicity of the fractions and isolated compounds was also determined on KB and Vero cell lines in order to determine the cytotoxicity/activity ratio of each one. ConclusionsThe results obtained with samvisterin (2) show that this new compound is the most promising of the series, with a weak cytotoxicity leading to the best selectivity index values.

Antiplasmodial activity of compounds isolated from Elaeagnus umbellata

The study of the chemical constituents of the whole plant of Elaeagnus umbellata has resulted in the isolation and characterization of three coumarins, namely, 7-Hydroxy-chromen-2-one (1), 7, 8-Dihyroxy-chromen-2-one (2), 3-(2,2,3,4,5-Pentahydroxy-hexyloxy)-chromen-2-one (3) and an anthraquinone (4) together with β-sitosterol glucopyranoside (5) and lupeol (6). The structural elucidation of the isolated compounds was established based on spectroscopic studies. The in vitro antimalarial activity of compounds 1 to 4 againstPlasmodium falciparum shows partial suppression of parasitic growth. Key words: Elaeagnus umbellata, coumarins, anti-malarial activity.

Phytochemical and Biological Activity Studies of the Bhutanese Medicinal Plant Corydalis crispa

The chemical constituents and biological activities of Corydalis crispa (Fumariaceae) were investigated for the first time. The phytochemical study resulted in the isolation of nine known isoquinoline alkaloids: protopine (1), 13-oxoprotopine (2), 13-oxocryptopine (3), stylopine (4), coreximine (5), rheagenine (6), ochrobirine (7), sibiricine (8) and bicuculline (9), with complete NMR data for 2 and 3 provided here for the first time. Crude extracts exhibitedsignificant anti-inflammatory (p < 0.01) activity against TNF-alpha production in LPS activated THP-1 cells. The acetylcholinesterase inhibitory activity of compounds 2, 4 and 7 and the antiplasmodial activity of compound 5 against P. falciparum strains TM4/8.2 and K1CB1 (multidrug resistant strain) are reported here for the first time. Stylopine (4) did not show antimalarial activity against the K1CB1 strain in contrast to a previous report. This study generated a scientific basis for the use of this plant in Bhutanese traditional medicine, either individually or in combination with other medicinal ingredients to treat a broad range of disorders. This study also identified compound 5 as potential new antimalarial lead compound.

Antiplasmodial activity of compounds from Drypetes gerrardii

0009-3130/12/4802-0339 2012 Springer Science+Business Media, Inc. 1) Department of Chemistry, Kenyatta University, P.O. Box 43844-00100, Nairobi, Kenya; 2) Department of Chemistry, Universitat Paderborn, Warburger Street 100, 33098 Paderborn, Germany, e-mail: Hidayat110@gmail.com; 3) Department of Biological Sciences and Chemistry, College of Arts and Sciences University of Nizwa, Birkat Al-Mouz, PC 616, Oman; 4) Centre for Traditional Medicine and Drug Research, Kenya Medical Research Institute, P. O. Box 54840-00200, Nairobi, Kenya; 5) NUST Center of Virology and Immunology, National University of Science and Technology, H-12, Islamabad, Pakistan. Published in Khimiya Prirodnykh Soedinenii, No. 2, March–April, 2012, pp. 304–305. Original article submitted January 4, 2011. Chemistry of Natural Compounds, Vol. 48, No. 2, May, 2012 [Russian original No. 2, March–April, 2012]

Antiplasmodial activity of quinones: Roles of aziridinyl substituents and the inhibition of Plasmodium falciparum glutathione reductase

Although quinones have been the subject of great interest as possible antimalarial agents, the mechanism of their antimalarial activity is poorly understood. Flavoenzyme electrontransferase-catalyzed redox cycling of quinones, and their inhibition of the antioxidant flavoenzyme glutathione reductase (GR, EC 1.8.1.7) have been proposed as possible mechanisms. Here, we have examined the activity of a number of quinones, including the novel antitumor agent RH1, against the malaria parasite Plasmodium falciparum strain FcB1 in vitro, their single-electron reduction rates by P. falciparum ferredoxin:NADP + reductase ( PfFNR, EC 1.18.1.2), and their ability to inhibit P. falciparum GR . The multiparameter statistical analysis of our data implies, that the antiplasmodial activity of fully-substituted quinones ( n = 15) is relatively independent from their one-electron reduction potential ( E 7 1 ). The presence of aziridinyl groups in quinone ring increased their antiplasmodial activity. Since aziridinyl-substituted quinones do not possess enhanced redox cycling activity towards PfFNR, we propose that they could act as as DNA-alkylating agents after their net two-electron reduction into aziridinyl-hydroquinones. We found that under the partial anaerobiosis, i.e., at the oxygen concentration below 40–50 μM, this reaction may be carried out by single-electron transferring flavoenzymes present in P. falciparum, like PfFNR. Another parameter increasing the antiplasmodial activity of fully-substituted quinones is an increase in their potency as P. falciparum GR inhibitors, which was revealed using multiparameter regression analysis. To our knowledge, this is the first quantitative demonstration of a link between the antiplasmodial activity of compounds and GR inhibition.

In vitro antiplasmodial activity of extract and constituents from Esenbeckia febrifuga, a plant traditionally used to treat malaria in the Brazilian Amazon

Esenbeckia febrifuga (Rutaceae) is a plant traditionally used to treat malaria in the Brazilian Amazon region. Ethanol extract of stems displayed a good antiplasmodial activity against Plasmodium falciparum strains W-2 (IC(50) 15.5+/-0.71 microg/ml) and 3 D7 (IC(50) 21.0+/-1.4 microg/ml). Two coumarins (bergaptene 1 and isopimpinellin 2), five alkaloids (flindersiamine 3, kokusaginine 4, skimmiamine 5, gamma-fagarine 6 and 1-hydroxy-3-methoxy-N-methylacridone, 7), besides a limonoid (rutaevine 8), have been isolated for the first time from this species. Antiplasmodial activity of compounds 3, 5-8 has been evaluated in vitro against P. falciparum strains (W-2 and 3D7) and the furoquinolines 5 and 6 were the most potent displaying IC(50) values <50 microg/ml; flindersiamine (3) showed a weak activity while alkaloid 7 and rutaevine (8) were inactive (IC(50)>100 microg/ml).