scholarly journals The Effect of Aqueous Extract of Cinnamon on the Metabolome ofPlasmodium falciparumUsing1HNMR Spectroscopy

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Shirin Parvazi ◽  
Sedigheh Sadeghi ◽  
Mehri Azadi ◽  
Maryam Mohammadi ◽  
Mohammad Arjmand ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Aqueous Extract ◽  
Drug Targets ◽  
Inhibitory Concentration ◽  
Biological Fluids ◽  
Medicinal Herbs ◽  
New Drugs ◽  
Lysine Biosynthesis ◽  
Glutathione Metabolism

Malaria is responsible for estimated 584,000 deaths in 2013. Researchers are working on new drugs and medicinal herbs due to drug resistance that is a major problem facing them; the search is on for new medicinal herbs. Cinnamon is the bark of a tree with reported antiparasitic effects. Metabonomics is the simultaneous study of all the metabolites in biological fluids, cells, and tissues detected by high throughput technology. It was decided to determine the mechanism of the effect of aqueous extract of cinnamon on the metabolome ofPlasmodium falciparum in vitrousing1HNMR spectroscopy. Prepared aqueous extract of cinnamon was added to a culture ofPlasmodium falciparum3D7 and its 50% inhibitory concentration determined, and, after collection, their metabolites were extracted and1HNMR spectroscopy by NOESY method was done. The spectra were analyzed by chemometric methods. The differentiating metabolites were identified using Human Metabolome Database and the metabolic cycles identified by Metaboanalyst. 50% inhibitory concentration of cinnamon onPlasmodium falciparumwas 1.25 mg/mL withp<0.001. The metabolites were identified as succinic acid, glutathione, L-aspartic acid, beta-alanine, and 2-methylbutyryl glycine. The main metabolic cycles detected were alanine and aspartame and glutamate pathway and pantothenate and coenzyme A biosynthesis and lysine biosynthesis and glutathione metabolism, which are all important as drug targets.

scholarly journals In Vitro Activities of Piperaquine and Other 4-Aminoquinolines against Clinical Isolates of Plasmodium falciparum in Cameroon

2003 ◽  
Vol 47 (4) ◽  
pp. 1391-1394 ◽  
Author(s):  
Leonardo K. Basco ◽  
Pascal Ringwald
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Concentration ◽  
Geometric Mean ◽  
Central Africa ◽  
New Drugs ◽  
Clinical Isolates ◽  
Highly Active ◽  
Synthetic Drug ◽  
Further Development

ABSTRACT The spread of chloroquine-resistant Plasmodium falciparum calls for a constant search for new drugs. The in vitro activity of piperaquine, a new Chinese synthetic drug belonging to the bisquinolines, was evaluated in 103 fresh clinical isolates of P. falciparum in Cameroon, Central Africa, and compared with that of other 4-aminoquinoline and Mannich base derivatives and dihydroartemisinin. Piperaquine was highly active (geometric mean 50% inhibitory concentration, 38.9 nmol/liter; range, 7.76 to 78.3 nmol/liter) and equally active (P > 0.05) against the chloroquine-sensitive and the chloroquine-resistant isolates. There was a significant but low correlation of response between chloroquine and piperaquine (r = 0.257, P < 0.05). These results suggest that further development of piperaquine, in combination with dihydroartemisinin, holds promise for use in chloroquine-resistant regions of endemicity.

scholarly journals Diversity-oriented synthesis derived indole based spiro and fused small molecules kills artemisinin-resistant Plasmodium falciparum

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Akshaykumar Nayak ◽  
Himani Saxena ◽  
Chandramohan Bathula ◽  
Tarkeshwar Kumar ◽  
Souvik Bhattacharjee ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Small Molecules ◽  
New Drugs ◽  
Developmental Cycle ◽  
Oxygen Species ◽  
Compound Library ◽  
Diversity Oriented Synthesis ◽  
Resistant Strains ◽  
Acid Catalyzed

Abstract Background Despite numerous efforts to eradicate the disease, malaria continues to remain one of the most dangerous infectious diseases plaguing the world. In the absence of any effective vaccines and with emerging drug resistance in the parasite against the majority of anti-malarial drugs, the search for new drugs is urgently needed for effective malaria treatment. Methods The goal of the present study was to examine the compound library, based on indoles generated through diversity-oriented synthesis belonging to four different architecture, i.e., 1-aryltetrahydro/dihydro-β-carbolines and piperidine/pyrrolidine-fused indole derivatives, for their in vitro anti-plasmodial activity. Trifluoroacetic acid catalyzed transformation involving tryptamine and various aldehydes/ketones provided the library. Results Among all the compounds screened, 1-aryltetrahydro-β-carbolines 2 and 3 displayed significant anti-plasmodial activity against both the artemisinin-sensitive and artemisinin-resistant strain of Plasmodium falciparum. It was observed that these compounds inhibited the overall parasite growth in intra-erythrocytic developmental cycle (IDC) via reactive oxygen species-mediated parasitic death and thus could be potential anti-malarial compounds. Conclusion Overall the compounds 2 and 3 identified in this study shows promising anti-plasmodial activity that can kill both artemisinin-sensitive and artemisinin-resistant strains of P. falciparum.

scholarly journals Assessment of the Drug Susceptibility of Plasmodium falciparum Clinical Isolates from Africa by Using a Plasmodium Lactate Dehydrogenase Immunodetection Assay and an Inhibitory Maximum Effect Model for Precise Measurement of the 50-Percent Inhibitory Concentration

2006 ◽  
Vol 50 (10) ◽  
pp. 3343-3349 ◽  
Author(s):  
Halima Kaddouri ◽  
Serge Nakache ◽  
Sandrine Houzé ◽  
France Mentré ◽  
Jacques Le Bras
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Lactate Dehydrogenase ◽  
Active Metabolite ◽  
Inhibitory Concentration ◽  
Drug Susceptibility ◽  
Maximum Effect ◽  
Malaria Parasites ◽  
Effect Model

ABSTRACT The extension of drug resistance among malaria-causing Plasmodium falciparum parasites in Africa necessitates implementation of new combined therapeutic strategies. Drug susceptibility phenotyping requires precise measurements. Until recently, schizont maturation and isotopic in vitro assays were the only methods available, but their use was limited by technical constraints. This explains the revived interest in the development of replacement methods, such as the Plasmodium lactate dehydrogenase (pLDH) immunodetection assay. We evaluated a commercially controlled pLDH enzyme-linked immunosorbent assay (ELISA; the ELISA-Malaria antigen test; DiaMed AG, Cressier s/Morat, Switzerland) to assess drug susceptibility in a standard in vitro assay using fairly basic laboratory equipment to study the in vitro resistance of malaria parasites to major antimalarials. Five Plasmodium falciparum clones and 121 clinical African isolates collected during 2003 and 2004 were studied by the pLDH ELISA and the [8-3H]hypoxanthine isotopic assay as a reference with four antimalarials. Nonlinear regression with a maximum effect model was used to estimate the 50% inhibitory concentration (IC50) and its confidence intervals. The two methods were observed to have similar reproducibilities, but the pLDH ELISA demonstrated a higher sensitivity. The high correlation (r = 0.98) and the high phenotypic agreement (κ = 0.88) between the two methods allowed comparison by determination of the IC50s. Recently collected Plasmodium falciparum African isolates were tested by pLDH ELISA and showed drug resistance or decreased susceptibilities of 62% to chloroquine and 11.5% to the active metabolite of amodiaquine. No decreased susceptibility to lumefantrine or the active metabolite of artemisinin was detected. The availability of this simple and highly sensitive pLDH immunodetection assay will provide an easier method for drug susceptibility testing of malaria parasites.

scholarly journals A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis

2014 ◽  
Vol 59 (1) ◽  
pp. 356-364 ◽  
Author(s):  
Wesley Wu ◽  
Zachary Herrera ◽  
Danny Ebert ◽  
Katie Baska ◽  
Seok H. Cho ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Drug ◽  
Drug Targets ◽  
Specific Activity ◽  
Drug Candidate ◽  
Content Type ◽  
Chemical Rescue ◽  
Growth Inhibitory ◽  
Parasite Populations

ABSTRACTThe apicoplast is an essential plastid organelle found inPlasmodiumparasites which contains several clinically validated antimalarial-drug targets. A chemical rescue screen identified MMV-08138 from the “Malaria Box” library of growth-inhibitory antimalarial compounds as having specific activity against the apicoplast. MMV-08138 inhibition of blood-stagePlasmodium falciparumgrowth is stereospecific and potent, with the most active diastereomer demonstrating a 50% effective concentration (EC50) of 110 nM. Whole-genome sequencing of 3 drug-resistant parasite populations from two independent selections revealed E688Q and L244I mutations inP. falciparumIspD, an enzyme in the MEP (methyl-d-erythritol-4-phosphate) isoprenoid precursor biosynthesis pathway in the apicoplast. The active diastereomer of MMV-08138 directly inhibited PfIspD activityin vitrowith a 50% inhibitory concentration (IC50) of 7.0 nM. MMV-08138 is the first PfIspD inhibitor to be identified and, together with heterologously expressed PfIspD, provides the foundation for further development of this promising antimalarial drug candidate lead. Furthermore, this report validates the use of the apicoplast chemical rescue screen coupled with target elucidation as a discovery tool to identify specific apicoplast-targeting compounds with new mechanisms of action.

scholarly journals IN VITRO POTENCY AND TOXICITY OF STREPTOMYCES SP. FERMENTATION PRODUCT AS AN ANTIMALARIAL THERAPY AGAINST PLASMODIUM FALCIPARUM

2019 ◽  
pp. 251-255
Author(s):  
YUNI SETYANINGSIH ◽  
ABDUL LATIF ◽  
HENDRI ASTUTY ◽  
DIN SYAFRUDDIN ◽  
PUJI BUDI SETIA ASIH
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Concentration ◽  
Toxicity Tests ◽  
Streptomyces Sp ◽  
No Formation ◽  
Fermentation Product ◽  
Transmission Electron ◽  
In Vitro Technique ◽  
Antimalarial Therapy

Objective: This research aims to study the activity of a Streptomyces sp. fermentation product as an antimalarial modality in HepG2 cells.Methods: The effects of the product against Plasmodium falciparum 3D7 were examined using an in vitro technique parasite. The potency of theStreptomyces sp. fermentation product was examined by determining the half maximal inhibitory concentration (IC50), and the mechanism wasstudied using transmission electron microscopy (TEM). Toxicity tests were also conducted.Results: The Streptomyces sp. fermentation product had an IC50 of 0.001 μg/ml against the parasite, versus values of 0.054 and 0.022 μg/ml forquinidine and prodigiosin, respectively. TEM revealed no formation of hemozoin. The Streptomyces sp. fermentation product was non-toxic in HepG2cells based on its cytotoxicity concentration 50% of 1.380 μg/ml.Conclusion: The Streptomyces sp. fermentation product has potential as a potent and non-toxic antimalarial therapy.

scholarly journals In VitroandIn VivoAntimalarial Efficacies of Optimized Tetracyclines

2013 ◽  
Vol 57 (7) ◽  
pp. 3131-3136 ◽  
Author(s):  
Michael P. Draper ◽  
Beena Bhatia ◽  
Haregewein Assefa ◽  
Laura Honeyman ◽  
Lynne K. Garrity-Ryan ◽  
...  
Keyword(s):  
Plasmodium Berghei ◽  
Inhibitory Concentration ◽  
New Drugs ◽  
Malaria Parasites ◽  
Content Type ◽  
Antimalarial Agents ◽  
Content Model ◽  
Safety Margins ◽  
Malaria Model

ABSTRACTWith increasing resistance to existing antimalarials, there is an urgent need to discover new drugs at affordable prices for countries in which malaria is endemic. One approach to the development of new antimalarial drugs is to improve upon existing antimalarial agents, such as the tetracyclines. Tetracyclines exhibit potent, albeit relatively slow, action against malaria parasites, and doxycycline is used for both treatment (with other agents) and prevention of malaria. We synthesized 18 novel 7-position modified tetracycline derivatives and screened them for activity against cultured malaria parasites. Compounds with potentin vitroactivity and other favorable drug properties were further tested in a rodent malaria model. Ten compounds inhibited the development of culturedPlasmodium falciparumwith a 50% inhibitory concentration (IC50) after 96 h of incubation of <30 nM, demonstrating activity markedly superior to that of doxycycline (IC50at 96 h of 320 nM). Most compounds showed little mammalian cell cytotoxicity and no evidence ofin vitrophototoxicity. In a murinePlasmodium bergheimodel, 13 compounds demonstrated improved activity relative to that of doxycycline. In summary, 7-position modified tetracyclines offer improved activity against malaria parasites compared to doxycycline. Optimized compounds may allow lower doses for treatment and chemoprophylaxis. If safety margins are adequate, dosing in children, the group at greatest risk for malaria in countries in which it is endemic, may be feasible.

scholarly journals Antifungal Properties and Target Evaluation of Three Putative Bacterial Histidine Kinase Inhibitors

1999 ◽  
Vol 43 (7) ◽  
pp. 1700-1703 ◽  
Author(s):  
Robert J. Deschenes ◽  
Hong Lin ◽  
Addison D. Ault ◽  
Jan S. Fassler
Keyword(s):  
Histidine Kinase ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Inhibitory Concentration ◽  
Drug Efficacy ◽  
Antibacterial Drug ◽  
Histidine Kinases ◽  
Antifungal Properties ◽  
Two Component

ABSTRACT Histidine protein kinases have been explored as potential antibacterial drug targets. The recent identification of two-component histidine kinases in fungi has led us to investigate the antifungal properties of three bacterial histidine kinase inhibitors (RWJ-49815, RWJ-49968, and RWJ-61907). All three compounds were found to inhibit growth of the Saccharomyces cerevisiae and Candida albicans strains, with MICs ranging from 1 to 20 μg/ml. However, deletion of SLN1, the only histidine kinase inS. cerevisiae, did not alter drug efficacy. In vitro kinase assays were performed by using the Sln1 histidine kinase purified from bacteria as a fusion protein to glutathione S-transferase. RWJ-49815 and RWJ-49968 inhibited kinase a 50% inhibitory concentration of 10 μM, whereas RWJ-61907 failed to inhibit at concentrations up to 100 μM. Based on these results, we conclude that these compounds have antifungal properties; however, their mode of action appears to be independent of histidine kinase inhibition.

scholarly journals A Photoalkylative Fluorogenic Probe of Guttiferone A for Live Cell Imaging and Proteome Labeling in Plasmodium falciparum

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5139
Author(s):  
Romain Duval ◽  
Kevin Cottet ◽  
Magali Blaud ◽  
Anaïs Merckx ◽  
Sandrine Houzé ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Natural Product ◽  
Drug Targets ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Molecular Probe ◽  
Positive Functional ◽  
Fluorogenic Probe ◽  
Symphonia Globulifera

Guttiferone A (GA) 1, a polycyclic polyprenylated acylphloroglucinol (PPAP) isolated from the plant Symphonia globulifera (Clusiaceae), constitutes a novel hit in antimalarial drug discovery. PPAPs do not possess identified biochemical targets in malarial parasites up to now. Towards this aim, we designed and evaluated a natural product-derived photoactivatable probe AZC-GA 5, embedding a photoalkylative fluorogenic motif of the 7-azidocoumarin (AZC) type, devoted to studying the affinity proteins interacting with GA in Plasmodium falciparum. Probe 5 manifested a number of positive functional and biological features, such as (i) inhibitory activity in vitro against P. falciparum blood-stages that was superimposable to that of GA 1, dose–response photoalkylative fluorogenic properties (ii) in model conditions using bovine serum albumin (BSA) as an affinity protein surrogate, (iii) in live P. falciparum-infected erythrocytes, and (iv) in fresh P. falciparum cell lysate. Fluorogenic signals by photoactivated AZC-GA 5 in biological settings were markedly abolished in the presence of excess GA 1 as a competitor, indicating significant pharmacological specificity of the designed molecular probe relative to the native PPAP. These results open the way to identify the detected plasmodial proteins as putative drug targets for the natural product 1 by means of proteomic analysis.

In vitro susceptibility of Gabonese wild isolates of Plasmodium falciparum to artemether, and comparison with chloroquine, quinine, halofantrine and amodiaquine

Parasitology ◽  
1998 ◽  
Vol 117 (6) ◽  
pp. 541-545 ◽  
Author(s):  
B. PRADINES ◽  
M. MABIKA MAMFOUMBI ◽  
D. PARZY ◽  
M. OWONO MEDANG ◽  
C. LEBEAU ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Concentration ◽  
Narrow Range ◽  
Drug Susceptibility ◽  
Drug Uptake ◽  
Cross Resistance ◽  
In Vitro Susceptibility ◽  
Positive Correlation ◽  
Common Features

The in vitro activity of artemether against 63 African isolates of Plasmodium falciparum from Libreville, Gabon was evaluated using an isotopic drug susceptibility semi-microtest. The 50% inhibitory concentration (IC50) values for artemether were in a narrow range from 0·8 to 34·8 nm (mean IC50 5·0 nm) and the 95% confidence interval (CI95%) was 3·6–6·3 nm. In vitro decreased susceptibility or resistance were observed with artemether (14%), to chloroquine (90%), to quinine (32%). Isolate susceptibility to amodiaquine and halofantrine was high i.e. 100% and 98%, respectively. There was a significant positive correlation between responses to artemether and amodiaquine (r2=0·45, P<0·001), artemether and chloroquine (r2=0·36, P<0·001), artemether and quinine (r2=0·31, P<0·001), and artemether and halofantrine r2=0·19, P<0·01). Positive correlation between these drugs suggests in vitro cross-resistance or at least common features in drug uptake and/or mode of action or resistance.

scholarly journals Plasmodium falciparum: In Vitro Cytotoxicity Testing Using MTT

1998 ◽  
Vol 3 (1) ◽  
pp. 49-53 ◽  
Author(s):  
J. Enrico Lazaro ◽  
Frederick Gay
Keyword(s):  
Plasmodium Falciparum ◽  
Culture System ◽  
Inhibitory Concentration ◽  
In Vitro Cytotoxicity ◽  
Mtt Method ◽  
Diphenyltetrazolium Bromide ◽  
Wide Range ◽  
In Vitro Culture System ◽  
Comparative Results

The microculture tetrazolium assay using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) was used to estimate the 50% inhibitory concentration of chloroquine, quinine, artemisinin, and atovaquone using a Plasmodium falciparum in vitro culture system. The MTT assay was compared to the standard tritiated hypoxan-thine assay and to a previously described method, the 2,2′-di-p-nitrophenyl-5,5′-diphenyl-3,3′-[3,3′-dimethoxy-4,4′-diphenylenel-ditetrazolium chloride (NBT) assay. In general, the results show that the three assays generate comparative results. The results of this study suggest that the MTT method is able to give a profile of cytotoxic dose response effects over a wide range of concentrations of a drug. The method may be used in work that does not require extreme pre-cision and sensitivity, for instance, as a portable rapid screen to assay natural products for in vitro cytotoxic ac-tivity against Plasmodium falciparum.

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