Antiplasmodial activity against resistant strains, toxicity and effect on mouse liver enzymes of extracts of Terminalia species found in Southwest Cameroon

Introduction: Terminalia species have the potential to be exploited in phytomedicine based on their several pharmacological properties including antiplasmodial activity. However, there is need for more data on their antiplasmodial activity and toxicity. This study evaluated the antiplasmodial activities of Terminalia catappa and Terminalia superba found in the coastal area of Cameroon on resistant strains of Plasmodium falciparum not previously tested, and their toxicity. Methods: Three leaf extracts of each plant prepared separately using three organic solvents were screened in vitro on 3 strains of P. falciparum: chloroquine-sensitive 3D7, chloroquine-resistant Dd2 and multi-drug resistant W2mef using the parasite growth inhibition assay. Antiplasmodial activity was assessed using fluorescence microscopy and the parasite lactate dehydrogenase assay. Cytotoxicity of active extracts was assessed on LLC-MK2 monkey kidney epithelial cells and acute toxicity including effect on some liver enzymes in BALB/c mice. Results: The methanol extracts of both plants showed the highest antiplasmodial activity (IC50 between 5.03-9.76 μg/mL) on the three parasite strains. The methanol extracts showed high selectivity for parasites with selectivity index values ranging from 40 to 80 indicating very low risk of toxicity. There was no mortality or adverse effect and no significant effect on the liver enzymes, alanine aminotransferase (P = 0.506) and aspartate aminotransferase (P = 0.243). Conclusion: The antiplasmodial activity, high selectivity and no adverse effects for T. catappa and T. superba demonstrate the potential for use of these plants in traditional treatment of malaria, further development into a phytomedicine against malaria and as source of new antimalarial lead.

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In vitro Antimalarial Evaluations and Cytotoxicity Investigations of Carica papaya Leaves and Carpaine

Natural Product Communications ◽

10.1177/1934578x1901400110 ◽

2019 ◽

Vol 14 (1) ◽

pp. 1934578X1901400 ◽

Cited By ~ 5

Author(s):

Woon-Chien Teng ◽

Wilson Chan ◽

Rossarin Suwanarusk ◽

Alice Ong ◽

Han-Kiat Ho ◽

...

Keyword(s):

Carica Papaya ◽

High Selectivity ◽

Scientific Basis ◽

Efficacy And Safety ◽

Leaf Extracts ◽

Traditional Use ◽

Human Red Blood Cells ◽

Bioassay Guided Fractionation ◽

Further Development

The objective of this study is to evaluate the antimalarial property of Carica papaya L. leaf extracts and the cytotoxicity of active samples. C. papaya leaves were extracted and screened against Plasmodium falciparum 3D7 and Dd2 strains. Bioassay-guided fractionation was carried out. The dichloromethane extract of C. papaya leaves showed significant antiplasmodial activity against P. falciparum 3D7 and Dd2. Successful bioassay-guided fractionation afforded a fraction three to seven times more active than the dichloromethane extract. Carpaine was isolated from the most active alkaloidal extract and identified in the active fraction and dichloromethane leaf extract. The cytotoxicity of active samples was evaluated against NL20 cells. A haemolysis assay was performed on carpaine. Carpaine exhibited good activity against both strains of P. falciparum with IC50 of 2.01 ± 0.18 μg/mL (4.21 μM) and 2.19 ± 0.60 μg/mL (4.57 μM) against 3D7 and Dd2 strains respectively. It exhibited high selectivity for the parasite and was non-toxic to healthy uninfected human red blood cells. This is the first study investigating the haemolysis potential of carpaine. The results provide a scientific basis for the traditional use of C. papaya leaves for malaria treatment. More work is required to evaluate the efficacy and safety of carpaine for further development into potential new antimalarial drugs.

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1360. Antimicrobial Activity of Cefepime in Combination with VNRX-5133 Against a Global Collection of Enterobacteriaceae Including Resistant Phenotypes

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1191 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S416-S417 ◽

Cited By ~ 3

Author(s):

Meredith Hackel ◽

Dan Sahm

Keyword(s):

Vitro Activity ◽

In Vitro Activity ◽

First Line ◽

First Line Therapy ◽

Carbapenem Resistant ◽

Line Therapy ◽

Resistant Strains ◽

Further Development ◽

Dose Dependent

Abstract Background VNRX-5133 is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with potent and selective direct inhibitory activity against both serine- and metallo-β-lactamases (Ambler Classes A, B, C, and D). In this analysis, we evaluated the activity of cefepime (FEP) in combination with VNRX-5133 and comparators against 1,120 recent Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Methods MICs of FEP with VNRX-5133 fixed at 4 µg/mL (FEP/VNRX-5133) were determined following CLSI M07-A10 guidelines against 1,120 Enterobacteriaceae from community and hospital infections collected globally in 2012–2013. Resistant phenotypes were based on 2017 CLSI breakpoints. As FEP/VNRX-5133 breakpoints have not yet been established, the FEP 2 g q8h susceptible dose-dependent (SDD) breakpoint of ≤8 µg/mL was considered for comparative purposes. Results FEP/VNRX-5133 showed potent in vitro activity against drug-resistant subsets of Enterobacteriaceae, with MIC90 values ranging from 1 µg/mL against ceftazidime-, levofloxacin-, or piperacillin–tazobactam-nonsusceptible isolates, to 8 µg/mL against meropenem-nonsusceptible isolates. FEP/VNRX-5133 inhibited >93% of all resistant subsets at ≤8 µg/mL. Conclusion Cefepime in combination with VNRX-5133 demonstrated potent in vitro activity against Enterobacteriaceae, including cephalosporin-, fluoroquinolone- and carbapenem-resistant (CRE) isolates. Because this drug combination exhibited substantial potential for the treatment of infections caused by isolates often resistant to first-line therapy, further development is warranted. Disclosures M. Hackel, IHMA, Inc.: Employee, Salary. VenatoRx: Consultant, Consulting fee. D. Sahm, IHMA, Inc.: Employee, Salary. VenatoRx: Consultant, Consulting fee.

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Comparative In Vitro Activities of AC98-6446, a Novel Semisynthetic Glycopeptide Derivative of the Natural Product Mannopeptimycin α, and Other Antimicrobial Agents against Gram-Positive Clinical Isolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.3.739-746.2004 ◽

2004 ◽

Vol 48 (3) ◽

pp. 739-746 ◽

Cited By ~ 41

Author(s):

Peter J. Petersen ◽

T. Z. Wang ◽

Russell G. Dushin ◽

Patricia A. Bradford

Keyword(s):

Natural Product ◽

Bactericidal Activity ◽

Antimicrobial Agents ◽

Marked Decrease ◽

Gram Positive ◽

Novel Structure ◽

Resistant Strains ◽

Vancomycin Resistant ◽

Further Development

ABSTRACT AC98-6446 is a novel semisynthetic cyclic glycopeptide antibiotic related to the natural product mannopeptimycin α (AC98-1). In the present study the activity of AC98-6446 was evaluated against a variety of recent clinical gram-positive pathogens including multiply resistant strains. AC98-6446 demonstrated similar potent activities against methicillin-susceptible and methicillin-resistant staphylococci and glycopeptide-intermediate staphylococcal isolates (MICs at which 90% of isolates are inhibited [MIC90s], 0.03 to 0.06 μg/ml). AC98-6446 also demonstrated good activities against both vancomycin-resistant and -susceptible strains of enterococci (MIC90s, 0.12 and 0.25 μg/ml, respectively) as well as against streptococcal strains (MIC90s, ≤ 0.008 to 0.03 μg/ml). AC98-6446 demonstrated bactericidal activity in terms of the reduction in the viable counts (>3 log10 CFU/ml) of staphylococcal and streptococcal isolates and a marked decrease in the viable counts of most enterococcal strains (from 0.2 to 2.5 log10 CFU/ml). Unlike vancomycin, which demonstrates time-dependent killing, AC98-6446 demonstrated concentration-dependent killing. The potent activity, novel structure, and bactericidal activity demonstrated by AC98-6446 make it an attractive candidate for further development.

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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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In vitro anti-malarial efficacy of chalcones: cytotoxicity profile, mechanism of action and their effect on erythrocytes

Malaria Journal ◽

10.1186/s12936-019-3060-z ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 5

Author(s):

Shweta Sinha ◽

Daniela I. Batovska ◽

Bikash Medhi ◽

B. D. Radotra ◽

Ashish Bhalla ◽

...

Keyword(s):

High Selectivity ◽

Selectivity Index ◽

Drug Resistant ◽

Inhibition Assay ◽

Substitution Pattern ◽

Diverse Range ◽

Mortality And Morbidity ◽

Viability Assay ◽

Resistant Strains

Abstract Background Malaria extensively leads to mortality and morbidity in endemic regions, and the emergence of drug resistant parasites is alarming. Plant derived synthetic pharmaceutical compounds are found to be a foremost research to obtain diverse range of potent leads. Amongst them, the chalcone scaffold is a functional template for drug discovery. The present study involves synthesis of ten chalcones with various substitution pattern in rings A and B and assessment of their anti-malarial efficacy against chloroquine sensitive and chloroquine resistant strains as well as of their cytotoxicity and effect on haemozoin production. Methods The chalcones were synthesized by Claisen-Schmidt condensation between equimolar quantities of substituted acetophenones and aryl benzaldehydes (or indole-3-carboxaldehyde) and were screened for anti-malarial activity by WHO Mark III schizont maturation inhibition assay. The cytotoxicity profile of a HeLa cell line was evaluated through MTT viability assay and the selectivity index (SI) was calculated. Haemozoin inhibition assay was performed to illustrate mode of action on a Plasmodium falciparum strain. Results The IC50 values of all compounds were in the range 0.10–0.40 μg/mL for MRC-2 (a chloroquine sensitive strain) and 0.14–0.55 μg/mL for RKL-9 (a chloroquine resistant strain) of P. falciparum. All the chalcones showed low cellular toxicity with minimal haemolysis. The statistically significant reduction (p < 0.05) in the haemozoin production suggests a similar mechanism than that of chloroquine. Conclusions Out of ten chalcones, number 7 was found to be a lead compound with the highest potency (IC50 = 0.11 µg/mL), as compared to licochalcone (IC50 = 1.43 µg/mL) and with high selectivity index of 85.05.

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In Vitro Assessment of Antiplasmodial Activity and Cytotoxicity of Polyalthia longifolia Leaf Extracts on Plasmodium falciparum Strain NF54

Malaria Research and Treatment ◽

10.1155/2019/6976298 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Bethel Kwansa-Bentum ◽

Kojo Agyeman ◽

Jeffrey Larbi-Akor ◽

Claudia Anyigba ◽

Regina Appiah-Opong

Keyword(s):

Plasmodium Falciparum ◽

Ethyl Acetate ◽

Red Blood Cells ◽

Blood Cells ◽

Radical Scavenging ◽

Antimalarial Drugs ◽

Antiplasmodial Activity ◽

Leaf Extracts ◽

Polyalthia Longifolia

Background. Malaria is one of the most important life-threatening infectious diseases in the tropics. In spite of the effectiveness of artemisinin-based combination therapy, reports on reduced sensitivity of the parasite to artemisinin in Cambodia and Thailand warrants screening for new potential antimalarial drugs for future use. Ghanaian herbalists claim that Polyalthia longifolia has antimalarial activity. Therefore, antiplasmodial activity, cytotoxic effects, and antioxidant and phytochemical properties of P. longifolia leaf extract were investigated in this study. Methodology/Principal Findings. Aqueous, 70% hydroethanolic and ethyl acetate leaf extracts were prepared using standard procedures. Antiplasmodial activity was assessed in vitro by using chloroquine-sensitive malaria parasite strain NF54. The SYBR® Green and tetrazolium-based calorimetric assays were used to measure parasite growth inhibition and cytotoxicity, respectively, after extract treatment. Total antioxidant activity was evaluated using a free radical scavenging assay. Results obtained showed that extracts protected red blood cells against Plasmodium falciparum mediated damage. Fifty percent inhibitory concentration (IC50) values were 24.0±1.08 μg/ml, 22.5±0.12 μg/ml, and 9.5±0.69 μg/ml for aqueous, hydroethanolic, and ethyl acetate extracts, respectively. Flavonoids, tannins, and saponins were present in the hydroethanolic extract, whereas only the latter was observed in the aqueous extract. Aqueous and hydroethanolic extracts showed stronger antioxidant activities compared to the ethyl acetate extract. Conclusions/Significance. The extracts of P. longifolia have antiplasmodial properties and low toxicities to human red blood cells. The extracts could be developed as useful alternatives to antimalarial drugs. These results support claims of the herbalists that decoctions of P. longifolia are useful antimalarial agents.

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Synthesis and Antimalarial Activities of Cyclen 4-Aminoquinoline Analogs

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01304-08 ◽

2009 ◽

Vol 53 (4) ◽

pp. 1320-1324 ◽

Cited By ~ 16

Author(s):

M. O. Faruk Khan ◽

Mark S. Levi ◽

Babu L. Tekwani ◽

Shabana I. Khan ◽

Eiichi Kimura ◽

...

Keyword(s):

Mammalian Cells ◽

High Selectivity ◽

Antimalarial Activity ◽

New Class ◽

Antimalarial Agents ◽

Sensitive Clone ◽

Resistant Strains ◽

Incorporation Assay

ABSTRACT In an attempt to augment the efficacy of 7-chloro 4-aminoquinoline analogs and also to overcome resistance to antimalarial agents, we synthesized three cyclen (1,4,7,10-tetraazacyclododecane) analogs of chloroquine [a bisquinoline derivative, 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline HBr, and a 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline-Zn2+ complex]. The bisquinoline displays the most potent in vitro and in vivo antimalarial activities. It displays 50% inhibitory concentrations (IC50s) of 7.5 nM against the D6 (chloroquine-sensitive) clone of Plasmodium falciparum and 19.2 nM against the W2 (chloroquine-resistant) clone, which are comparable to those of artemisinin (10.6 and 5.0 nM, respectively) and lower than those of chloroquine (10.7 and 87.2 nM, respectively), without any evidence of cytotoxicity to mammalian cells, indicating a high selectivity index (>1,333 against D6 clone and >521 against W2 clone). Potent antimalarial activities of the bisquinoline against chloroquine- and mefloquine-resistant strains of P. falciparum were also confirmed by in vitro [3H]hypoxanthine incorporation assay. The in vivo antimalarial activity of the bisquinoline, as determined in P. berghei-infected mice, is comparable to that of chloroquine (50% effective dose, ≤1.1 mg/kg when given orally); no apparent toxicity has been observed up to the highest dose tested (3 × 30 mg/kg). The bisquinoline inhibits in vitro hemozoin (β-hematin) formation with an IC50 of 1.1 μM, which is about 10-fold more potent than chloroquine (IC50 9.5 μM). Overall, this article describes the discovery of a new class of cyclen 4-aminoquinoline analogs as potent antimalarial drugs.

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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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An Optimized Bacteriophage Cocktail Can Effectively Control Salmonella in vitro and in Galleria mellonella

Frontiers in Microbiology ◽

10.3389/fmicb.2020.609955 ◽

2021 ◽

Vol 11 ◽

Author(s):

Janet Y. Nale ◽

Gurinder K. Vinner ◽

Viviana C. Lopez ◽

Anisha M. Thanki ◽

Preeda Phothaworn ◽

...

Keyword(s):

Galleria Mellonella ◽

Future Application ◽

Infection Model ◽

Prophylactic Regimen ◽

Phage Cocktail ◽

Resistant Strains ◽

Future Work ◽

Further Development

Salmonella spp. is a leading cause of gastrointestinal enteritis in humans where it is largely contracted via contaminated poultry and pork. Phages can be used to control Salmonella infection in the animals, which could break the cycle of infection before the products are accessible for consumption. Here, the potential of 21 myoviruses and a siphovirus to eliminate Salmonella in vitro and in vivo was examined with the aim of developing a biocontrol strategy to curtail the infection in poultry and swine. Together, the phages targeted the twenty-three poultry and ten swine prevalent Salmonella serotype isolates tested. Although individual phages significantly reduced bacterial growth of representative isolates within 6 h post-infection, bacterial regrowth occurred 1 h later, indicating proliferation of resistant strains. To curtail bacteriophage resistance, a novel three-phage cocktail was developed in vitro, and further investigated in an optimized Galleria mellonella larva Salmonella infection model colonized with representative swine, chicken and laboratory strains. For all the strains examined, G. mellonella larvae given phages 2 h prior to bacterial exposure (prophylactic regimen) survived and Salmonella was undetectable 24 h post-phage treatment and throughout the experimental time (72 h). Administering phages with bacteria (co-infection), or 2 h post-bacterial exposure (remedial regimen) also improved survival (73–100% and 15–88%, respectively), but was less effective than prophylaxis application. These pre-livestock data support the future application of this cocktail for further development to effectively treat Salmonella infection in poultry and pigs. Future work will focus on cocktail formulation to ensure stability and incorporation into feeds and used to treat the infection in target animals.

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