Antimalarial drug mefloquine kills both trophozoite and cyst stages of Entamoeba

The exploration of alternative antimalarial therapeutics is a requisite for the emergence of resistance against Artemisinin. Considering the required cost and time length of classical small molecule drug discovery process, phytochemical screening of traditionally used medicinal plant which are repertoire of active compounds with antimalarial activity has become popular. To investigate the antimalarial property of traditionally used medicinal plants, a number of Erythrina spp have been reviewed systematically where less studied E. fusca has been selected for further analysis. Phytochemical investigation yielded five compounds namely; Phaseolin, Phytol, β-amyrin, Lupeol, and Stigmasterol. In-vitro antimalarial drug sensitivity HRP-II ELISA was carried out against chloroquine (CQ) sensitive 3D7 and CQ-resistant Dd2 strains. Extracts showed significant antimalarial activity against 3D7 and Dd2 strains (IC50 4.94 – 22 µg/mL) and these compounds have been reported here for the first time. Molecular docking analysis showed high binding energy (−9.0 ± 0.32 kcal/mole) indicating high degree of interaction between Phaseolin and 14 clinically important Plasmodium falciparum proteins at the active site. Stable interaction was also observed between ligand and protein from molecular dynamics simulation analysis with high free energy (−75.156 ± 11.459) that substantiates the potential of Phaseolin as an antimalarial drug candidate.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03342-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 356-364 ◽

Cited By ~ 52

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.

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Evaluation of the in vitro activity of ceragenins against Trichomonas vaginalis

Acta Parasitologica ◽

10.1515/ap-2016-0049 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 2

Author(s):

Zubeyde Akin Polat ◽

Ali Cetin ◽

Poul B. Savage

Keyword(s):

Trichomonas Vaginalis ◽

Protozoan Parasite ◽

Vitro Activity ◽

In Vitro Activity

AbstractTrichomonosis, caused by the protozoan parasite

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Antineoplastic kinase inhibitors: A new class of potent anti-amoebic compounds

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0008425 ◽

2021 ◽

Vol 15 (2) ◽

pp. e0008425

Author(s):

Conall Sauvey ◽

Gretchen Ehrenkaufer ◽

Da Shi ◽

Anjan Debnath ◽

Ruben Abagyan

Keyword(s):

Kinase Inhibitors ◽

Model Organism ◽

Protozoan Parasite ◽

Drug Candidates ◽

New Class ◽

Alternative Approach ◽

The 1960S ◽

Approved Drugs ◽

Micromolar Range

Entamoeba histolytica is a protozoan parasite which infects approximately 50 million people worldwide, resulting in an estimated 70,000 deaths every year. Since the 1960s E. histolytica infection has been successfully treated with metronidazole. However, drawbacks to metronidazole therapy exist, including adverse effects, a long treatment course, and the need for an additional drug to prevent cyst-mediated transmission. E. histolytica possesses a kinome with approximately 300–400 members, some of which have been previously studied as potential targets for the development of amoebicidal drug candidates. However, while these efforts have uncovered novel potent inhibitors of E. histolytica kinases, none have resulted in approved drugs. In this study we took the alternative approach of testing a set of twelve previously FDA-approved antineoplastic kinase inhibitors against E. histolytica trophozoites in vitro. This resulted in the identification of dasatinib, bosutinib, and ibrutinib as amoebicidal agents at low-micromolar concentrations. Next, we utilized a recently developed computational tool to identify twelve additional drugs with human protein target profiles similar to the three initial hits. Testing of these additional twelve drugs led to the identification of ponatinib, neratinib, and olmutinib were identified as highly potent, with EC50 values in the sub-micromolar range. All of these six drugs were found to kill E. histolytica trophozoites as rapidly as metronidazole. Furthermore, ibrutinib was found to kill the transmissible cyst stage of the model organism E. invadens. Ibrutinib thus possesses both amoebicidal and cysticidal properties, in contrast to all drugs used in the current therapeutic strategy. These findings together reveal antineoplastic kinase inhibitors as a highly promising class of potent drugs against this widespread and devastating disease.

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A Tetrahydrophthalazinone Inhibitor of Phosphodiesterase with In Vitro Activity Against Intracellular Trypanosomatids

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00960-20 ◽

2020 ◽

Author(s):

Julianna Siciliano de Araújo ◽

Raiza Brandão Peres ◽

Patrícia Bernardino da Silva ◽

Marcos Meuser Batista ◽

Geert Jan Sterk ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Phosphodiesterase Inhibitor ◽

Drug Candidate ◽

In Vitro Activity ◽

Target Validation ◽

Activity Profile ◽

Intracellular Amastigotes ◽

Potential Activity ◽

Camp Levels

The phosphodiesterase inhibitor tetrahydrophthalazinone NPD-008 was explored by phenotypic in vitro screening, target validation and ultrastructural approaches against Trypanosoma cruzi. NPD-008 displayed activity against different forms and strains of T. cruzi (EC50 = 6.6 – 39.5 μM), increased cAMP levels of T. cruzi and its combination with Bz gave synergistic interaction. It was also moderately active against intracellular amastigotes of Leishmania amazonensis and L. infantum, confirming a potential activity profile as an antitrypanosomatid drug candidate.

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In Vitro Activity of Methanol Extract of Microalgae Hapalosiphon aureus Against Trichomonas vaginalis

10.32792/utq/utjsci/vol7/2/9 ◽

2020 ◽

pp. 34-36

Keyword(s):

Mass Spectrum ◽

Secondary Metabolites ◽

Natural Product ◽

Trichomonas Vaginalis ◽

Methanol Extract ◽

Protozoan Parasite ◽

In Vitro Activity ◽

Total Composition ◽

First Time

The present study targets the protozoan parasite Trichomonas vaginalis that causes a healthy problem among women and rarely among men, by the application of natural product or secondary metabolites extracted from the microalgae Hapalosiphon aureus for the first time in Iraq. methanol extract was explained high activity in three concentration recording 100% of parasite death at 200 µg\ml of methanol extract in about two days while 150 and 100 µg\ml of extract reports activity against the parasite after fourand fivedays post treatment respectively. GC- Mass spectrum of the methanol extract has explain presence of the compound (2- deca - 3,d- dienyloxy) carbonyl benzeoic acid in about 13.28 % from the total composition of methanol extract of microalgae.

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The Oral Antimalarial Drug Tafenoquine Shows Activity against Trypanosoma brucei

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00879-15 ◽

2015 ◽

Vol 59 (10) ◽

pp. 6151-6160 ◽

Cited By ~ 16

Author(s):

Luis Carvalho ◽

Marta Martínez-García ◽

Ignacio Pérez-Victoria ◽

José Ignacio Manzano ◽

Vanessa Yardley ◽

...

Keyword(s):

Trypanosoma Brucei ◽

Antimalarial Drug ◽

Protozoan Parasite ◽

Sleeping Sickness ◽

Phase Iii ◽

Content Type ◽

Clinical Phase ◽

Intracellular Ca ◽

Cytoplasmic Content

ABSTRACTThe protozoan parasiteTrypanosoma bruceicauses human African trypanosomiasis, or sleeping sickness, a neglected tropical disease that requires new, safer, and more effective treatments. Repurposing oral drugs could reduce both the time and cost involved in sleeping sickness drug discovery. Tafenoquine (TFQ) is an oral antimalarial drug belonging to the 8-aminoquinoline family which is currently in clinical phase III. We show here that TFQ efficiently kills differentT. bruceispp. in the submicromolar concentration range. Our results suggest that TFQ accumulates into acidic compartments and induces a necrotic process involving cell membrane disintegration and loss of cytoplasmic content, leading to parasite death. Cell lysis is preceded by a wide and multitarget drug action, affecting the lysosome, mitochondria, and acidocalcisomes and inducing a depolarization of the mitochondrial membrane potential, elevation of intracellular Ca2+, and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significantin vitroactivity againstT. brucei.

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