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.

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IN VITRO ANTIPLASMODIAL AND CYTOTOXIC ACTIVITIES OF A SUNGKAI (PERONEMA CANESCENS) LEAF EXTRACT

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2018v10i10.25124 ◽

2018 ◽

Vol 10 (10) ◽

pp. 109

Author(s):

Jhons Fatriyadi Suwandi ◽

Mahardika Agus Wijayanti ◽

Mustofa .

Keyword(s):

Plasmodium Falciparum ◽

Vero Cells ◽

In Vitro Cytotoxicity ◽

Selectivity Index ◽

Antiplasmodial Activity ◽

Cytotoxic Activities ◽

Aqueous Extracts ◽

Diphenyltetrazolium Bromide ◽

Ic50 Values

Objective: The aim of this study was to assess the antiplasmodial and cytotoxic activities and to evaluate the selectivity indices of acetone, ethanol and aqueous extracts of Peronema canescens leaves.Methods: Antiplasmodial activity was measured in vitro against Plasmodium falciparum strains D10 and FCR3 by 72 h incubation at 37 °C in a candle jar. Parasitaemia was calculated by counting the parasite numbers in thin smears. In vitro cytotoxicity was assayed in Vero cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and reading the absorbency at 595 nm with an ELISA reader. The assessed parameters included: 50% inhibitory concentration (IC50) of antiplasmodial activity, IC50 of cytotoxic activity and the selectivity index of the Peronema canescens leaf extract.Results: The IC50 values for the acetone, ethanol and aqueous extracts were 26.33±1.65, 37.96±8.17 and 12.26±1.05 μg/ml, respectively, against the Plasmodium falciparum D10 strain and 51.14±8.65, 70.22±14.13 and 34.85±6.04 μg/ml, respectively, against the FCR3 strain. For Vero cells, the IC50 values for the acetone, ethanol and aqueous extracts were 23.37±5.63, 629.46±24.85 and 634.00±144.82 μg/ml, respectively. The selectivity indices of these extracts were 0.89, 16.46 and 51.70, respectively, for the D10 strain and 0.46, 8.90 and 18.00, respectively, for the FCR3 strain.Conclusion: The aqueous extract of Peronema canescens leaves had the highest in vitro antiplasmodial activity and the best selectivity index.

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Synthesis of metergoline analogues and their evaluation as antiplasmodial agents

MedChemComm ◽

10.1039/c3md00310h ◽

2014 ◽

Vol 5 (2) ◽

pp. 165-170 ◽

Cited By ~ 1

Author(s):

Kawaljit Singh ◽

Gurminder Kaur ◽

Faith Mjambili ◽

Peter J. Smith ◽

Kelly Chibale

Keyword(s):

Cell Line ◽

Mammalian Cell ◽

High Selectivity ◽

Selectivity Index ◽

Antiplasmodial Activity ◽

Mammalian Cell Line

A series of metergoline analogues were synthesized and evaluatedin vitrofor antiplasmodial activity and cytotoxicity towards a mammalian cell line. Some of the compounds exhibited promising selective antiplasmodial activity along with a high selectivity index relative to metergoline.

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Synthesis of Novel 1,2,3-Triazole Derivatives of Isocoumarins and 3,4-Dihydroisocoumarin with Potential Antiplasmodial Activity In Vitro

Medicinal Chemistry ◽

10.2174/1573406416666200602161047 ◽

2020 ◽

Vol 16 ◽

Author(s):

Lucas da Silva Santos ◽

Matheus Fillipe Langanke de Carvalho ◽

Ana Claudia de Souza Pinto ◽

Amanda Luisa da Fonseca ◽

Julio César Dias Lopes ◽

...

Keyword(s):

Triazole Ring ◽

Antiplasmodial Activity ◽

World Health ◽

Dipolar Cycloaddition ◽

Terminal Alkynes ◽

The World ◽

Ic50 Values ◽

Derivatives Of ◽

Active Substances

Background: Malaria greatly affects the world health, having caused more than 228 million cases only in 2018. The emergence of drug resistance is one of the main problems in its treatment, demonstrating the urge for the development of new antimalarial drugs. Objective: Synthesis and in vitro antiplasmodial evaluation of triazole compounds derived from isocoumarins and a 3,4- dihydroisocoumarin. Method: The compounds were synthesized in 4 to 6-step reactions with the formation of the triazole ring via the Copper(I)-catalyzed 1,3-dipolar cycloaddition between isocoumarin or 3,4-dihydroisocoumarin azides and terminal alkynes. This key reaction provided compounds with an unprecedented connection of isocoumarin or 3,4-dihydroisocoumarin and the 1,2,3-triazole ring. The products were tested for their antiplasmodial activity against a Plasmodium falciparum chloroquine resistant and sensitive strains (W2 and 3D7, respectively). Results: Thirty-one substances were efficiently obtained by the proposed routes with an overall yield of 25-53%. The active substances in the antiplasmodial test displayed IC50 values ranging from 0.68-2.89 μM and 0.85-2.07 μM against W2 and 3D7 strains, respectively.

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New Antiproliferative Triflavanone from Thymelaea hirsuta—Isolation, Structure Elucidation and Molecular Docking Studies

Molecules ◽

10.3390/molecules26030739 ◽

2021 ◽

Vol 26 (3) ◽

pp. 739

Author(s):

Sameh S. Elhady ◽

Reda F. A. Abdelhameed ◽

Mayada M. El-Ayouty ◽

Amany K. Ibrahim ◽

Eman S. Habib ◽

...

Keyword(s):

Molecular Docking ◽

Liver Tumors ◽

Fold Increase ◽

In Vitro Cytotoxicity ◽

Mitogen Activated Protein Kinase ◽

Wild Plant ◽

Cytotoxic Activities ◽

Ic50 Values ◽

Thymelaea Hirsuta

In this study isolates from Thymelaea hirsuta, a wild plant from the Sinai Peninsula of Egypt, were identified and their selective cytotoxicity levels were evaluated. Phytochemical examination of the ethyl acetate (EtOAc) fraction of the methanolic (MeOH) extract of the plant led to the isolation of a new triflavanone compound (1), in addition to the isolation of nine previously reported compounds. These included five dicoumarinyl ethers found in Thymelaea: daphnoretin methyl ether (2), rutamontine (3), neodaphnoretin (4), acetyldaphnoretin (5), and edgeworthin (6); two flavonoids: genkwanin (7) and trans-tiliroside (8); p-hydroxy benzoic acid (9) and β sitosterol glucoside (10). Eight of the isolated compounds were tested for in vitro cytotoxicity against Vero and HepG2 cell lines using a sulforhodamine-B (SRB) assay. Compounds 1, 2 and 5 exhibited remarkable cytotoxic activities against HepG2 cells, with IC50 values of 8.6, 12.3 and 9.4 μM, respectively, yet these compounds exhibited non-toxic activities against the Vero cells. Additionally, compound 1 further exhibited promising cytotoxic activity against both MCF-7 and HCT-116 cells, with IC50 values of 4.26 and 9.6 μM, respectively. Compound 1 significantly stimulated apoptotic breast cancer cell death, resulting in a 14.97-fold increase and arresting 40.57% of the cell population at the Pre-G1 stage of the cell cycle. Finally, its apoptosis-inducing activity was further validated through activation of BAX and caspase-9, and inhibition of BCL2 levels. In silico molecular docking experiments revealed a good binding mode profile of the isolates towards Ras activation/pathway mitogen-activated protein kinase (Ras/MAPK); a common molecular pathway in the development and progression of liver tumors.

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In vitro antiplasmodial activity of ethanolic extracts of South Indian medicinal plants against Plasmodium falciparum

Asian Pacific Journal of Tropical Disease ◽

10.1016/s2222-1808(12)60043-7 ◽

2012 ◽

Vol 2 (3) ◽

pp. 180-183 ◽

Cited By ~ 18

Author(s):

Sundaram Ravikumar ◽

Samuel Jacob Inbaneson ◽

Palavesam Suganthi

Keyword(s):

Plasmodium Falciparum ◽

Medicinal Plants ◽

Antiplasmodial Activity ◽

South Indian ◽

Ethanolic Extracts ◽

Indian Medicinal Plants

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Matrix metalloproteinase-2 inhibition activity of Plukenetia volubilis L. leaves extract for anti-aging application

Food Research ◽

10.26656/fr.2017.5(4).077 ◽

2021 ◽

Vol 5 (4) ◽

pp. 120-126

Author(s):

N. Wuttisin ◽

T. Nararatwanchai ◽

A. Sarikaphuti

Keyword(s):

High Performance ◽

Antioxidant Property ◽

In Vitro Cytotoxicity ◽

Hot Water ◽

Matrix Metalloproteinase 2 ◽

Human Skin Fibroblast ◽

Inhibition Activity ◽

Hot Air ◽

Plukenetia Volubilis

Plukenetia volubilis L. leaves were part of the traditional diets in many countries. P. volubilis leaves were used to make tea and sold as local products in Thailand. There is less information on the composition of P. volubilis leaves. Previous study revealed that roasted leaves extract with hot water showed the highest antioxidant activity and the antioxidant property might be due to the presence of flavonoid. The present study was carried out to determine the quercetin content in P. volubilis leaves extract and evaluate the anti-aging potential activities including MMP-2 inhibition activity and telomerase stimulation activity. P. volubilis leaves were roasted in hot air oven and extracted with hot water. The extract was investigated for quercetin content by high-performance liquid chromatography (HPLC). In vitro cytotoxicity, MMP-2 inhibition activity and telomerase stimulation activity were determined for anti-aging properties. The results revealed that P. volubilis leaves contained quercetin 50.50±4.78 mg/g DW. The extract showed no cytotoxicity on human skin fibroblast with cell viability of 96.76-120.83%. It demonstrated the potential of MMP-2 inhibition (8.74±2.84%) activity but lower than ascorbic acid. P. volubilis leave extract did not have telomerase stimulation activity on the human Hela cell line. However, the results from this study have indicated the possibility of anti-aging potential of P. volubilis leaves extract.

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In vitro Assessment of Antiplasmodial Activity and Acute Oral Toxicity of Dissotis rotundifolia Extracts and Fractions on Plasmodium falciparum Strains

Journal of Applied Life Sciences International ◽

10.9734/jalsi/2020/v23i530161 ◽

2020 ◽

pp. 8-19

Author(s):

Rock Djehoue ◽

Rafiou Adamou ◽

Abdou Madjid O. Amoussa ◽

Adande A. Medjigbodo ◽

Anatole Laleye ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Acute Toxicity ◽

Ethanolic Extract ◽

Antiplasmodial Activity ◽

Oral Toxicity ◽

Aqueous Fraction ◽

Vector Borne Diseases ◽

Natural Substances ◽

Study Laboratory

Aim: Dissotis rotundifolia were selected after an ethnopharmacological survey conducted on plants used traditionally for malaria treatment in South Benin, with the aim of discovering new natural active extracts against malaria parasites. Place and Duration of Study: Laboratory of Biochemistry and Bioactive Natural Substances, University of Abomey-Calavi (Benin)/ Laboratory of Infectious Vector Borne Diseases, Regional Institute of Public Health (Benin)/ Laboratoire d’Histologie, de Cytogénétique et d’Embryologie, Faculté des Sciences de la Santé (Benin). The study was conduct from October 2018 to June 2019 in Benin. Methodology: The antiplasmodial activity of the plant extracts was evaluated using the parasite lactate dehydrogenase (pLDH) immunodetection assay. The extract with the best antiplasmodial activity were used on Wistar rats for acute toxicity. Results: Ethanolic extract of Dissotis rotundifolia showed promising activity (Isolate: IC50 = 22.58 ± 1.12 µg/mL; 3D7: IC50 = 6.81 ± 0.85 µg/mL) on Plasmodium falciparum compared to the aqueous extract (Isolate: IC50 > 100 µg/mL; 3D7: IC50> 100 µg/mL). The aqueous fraction of D. rotundifolia exhibit highly potent activity against P. falciparum strain (Isolate: IC50 > 100 µg/mL μg/mL; 3D7: IC50 = 4.05 ± 0.72 μg/mL). Haemolytic effect of actives extracts and fractions is less than 5%. Ethanolic extract of D. rotundifolia revealed no obvious acute toxicity in rat up to the highest dose administered (2000 mg/kg). Conclusion: This study justifies traditional uses of D. rotundifolia against malaria. A bioguided fractionation of these extracts would identify molecules responsible for their antiplasmodial activity. Moreover, these results could lead to the design of improved traditional medicines in the basis of this plant.

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Exploring heteroaromatic rings as a replacement for the labile amide of antiplasmodial pantothenamides

10.1101/2020.10.02.324079 ◽

2020 ◽

Author(s):

Jinming Guan ◽

Christina Spry ◽

Erick T. Tjhin ◽

Penghui Yang ◽

Tanakorn Kittikool ◽

...

Keyword(s):

Contact Time ◽

High Selectivity ◽

Amide Group ◽

Antiplasmodial Activity ◽

Time Data ◽

Facile Synthesis ◽

Isoxazole Derivative ◽

Nanomolar Range

ABSTRACTThe Plasmodium parasites that cause malaria are adept at developing resistance to antimalarial drugs, necessitating the search for new antiplasmodials. Although several amide analogs of pantothenate (pantothenamides) show potent antiplasmodial activity, hydrolysis by pantetheinases (or vanins) present in blood rapidly inactivates them. We report herein the facile synthesis and biological activity of a small library of pantothenamide analogs in which the labile amide group is replaced with a variety of heteroaromatic rings. Several of the new analogs display antiplasmodial activity in the nanomolar range against P. falciparum and/or P. knowlesi in the presence of pantetheinase. A previously reported triazole and an isoxazole derivative presented here were further characterized and found to possess high selectivity indices, medium or high Caco-2 permeability, and medium or low microsomal clearance in vitro. Although we show here that the two compounds fail to suppress proliferation of P. berghei in vivo, pharmacokinetic and contact time data presented provide a benchmark for the compound profile required to achieve antiplasmodial activity in mice and should facilitate lead optimization.

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Boromycin has Rapid-Onset Antibiotic Activity Against Asexual and Sexual Blood Stages of Plasmodium falciparum

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.802294 ◽

2022 ◽

Vol 11 ◽

Author(s):

Laís Pessanha de Carvalho ◽

Sara Groeger-Otero ◽

Andrea Kreidenweiss ◽

Peter G. Kremsner ◽

Benjamin Mordmüller ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Plasmodium Knowlesi ◽

Rapid Onset ◽

Multidrug Resistant ◽

Antiplasmodial Activity ◽

Onset Of Action ◽

Streptomyces Antibioticus ◽

Life Cycle Stages ◽

Almost All

Boromycin is a boron-containing macrolide antibiotic produced by Streptomyces antibioticus with potent activity against certain viruses, Gram-positive bacteria and protozoan parasites. Most antimalarial antibiotics affect plasmodial organelles of prokaryotic origin and have a relatively slow onset of action. They are used for malaria prophylaxis and for the treatment of malaria when combined to a fast-acting drug. Despite the success of artemisinin combination therapies, the current gold standard treatment, new alternatives are constantly needed due to the ability of malaria parasites to become resistant to almost all drugs that are in heavy clinical use. In vitro antiplasmodial activity screens of tetracyclines (omadacycline, sarecycline, methacycline, demeclocycline, lymecycline, meclocycline), macrolides (oleandomycin, boromycin, josamycin, troleandomycin), and control drugs (chloroquine, clindamycin, doxycycline, minocycline, eravacycline) revealed boromycin as highly potent against Plasmodium falciparum and the zoonotic Plasmodium knowlesi. In contrast to tetracyclines, boromycin rapidly killed asexual stages of both Plasmodium species already at low concentrations (~ 1 nM) including multidrug resistant P. falciparum strains (Dd2, K1, 7G8). In addition, boromycin was active against P. falciparum stage V gametocytes at a low nanomolar range (IC50: 8.5 ± 3.6 nM). Assessment of the mode of action excluded the apicoplast as the main target. Although there was an ionophoric activity on potassium channels, the effect was too low to explain the drug´s antiplasmodial activity. Boromycin is a promising antimalarial candidate with activity against multiple life cycle stages of the parasite.

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