scholarly journals Pyrrolopyrimidine vs Imidazole-Phenyl-Thiazole Scaffolds in Nonpeptidic Dimerization Inhibitors of Leishmania infantum Trypanothione Reductase

2019 ◽  
Vol 5 (6) ◽  
pp. 873-891 ◽  
Author(s):  
Alejandro Revuelto ◽  
Marta Ruiz-Santaquiteria ◽  
Héctor de Lucio ◽  
Ana Gamo ◽  
Alejandra A. Carriles ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Trypanothione Reductase ◽  
Dimerization Inhibitors

scholarly journals Comparison of hydrocarbon-and lactam-bridged cyclic peptides as dimerization inhibitors of Leishmania infantum trypanothione reductase

RSC Advances ◽  
2015 ◽  
Vol 5 (69) ◽  
pp. 55784-55794 ◽  
Author(s):  
Pedro A. Sánchez-Murcia ◽  
Marta Ruiz-Santaquiteria ◽  
Miguel A. Toro ◽  
Héctor de Lucio ◽  
María Ángeles Jiménez ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Cyclic Peptides ◽  
Side Chain ◽  
Trypanothione Reductase ◽  
Helical Peptides ◽  
Dimerization Inhibitors

Helical peptides stabilizedviaall-hydrocarbon or lactam side-chain bridging were investigated as disruptors ofLeishmania infantumtrypanothione reductase.

Novel Scaffolds for Leishmania infantum Trypanothione Reductase Inhibitors Derived from Brazilian Natural Products Biodiversity

2021 ◽  
Vol 18 (4) ◽  
pp. 398-418
Author(s):  
Vinícius Guimarães da Paixão ◽  
Samuel Silva da Rocha Pita
Keyword(s):  
Natural Products ◽  
Leishmania Infantum ◽  
In Vitro Assays ◽  
Current Therapy ◽  
Pharmacokinetic Analysis ◽  
Trypanothione Reductase ◽  
Resistant Species ◽  
Reductase Inhibitors ◽  
Thiol Redox

Background: Leishmania infantum causes the most lethal form of Leishmaniasis: Visceral leishmaniasis. Current therapy for this disease is related to the development of drug-resistant species and toxicity. Trypanothione Reductase (LiTR), a validated target for the drug discovery process, is involved with parasites' thiol-redox metabolism. Objective: In this study, through Virtual Screening employing two distinct Natural Products Brazilian databases, we aimed to identify novel inhibitor scaffolds against LiTR. Results: Thus, the “top 10” LiTR-ligand energies have been selected and their interaction profiles into LiTR sites through the AuPosSOM server have been verified. Finally, Pred-hERG, Aggregator Advisor, FAF-DRUGS, pkCSM and DataWarrior were employed and their results allowed us to evaluate, respectively, the cardiotoxicity, aggregation capacity, presence of false-positive compounds (PAINS) and their toxicities. Conclusion: Three molecules that overcame the in silico pharmacokinetic analysis and have a good interaction with LiTR, were chosen to use in vitro assays hoping that our computational results reported here would aid the development of new anti-leishmanial compounds.

scholarly journals Modeled structure of trypanothione reductase of Leishmania infantum

BMB Reports ◽  
2008 ◽  
Vol 41 (6) ◽  
pp. 444-447 ◽  
Author(s):  
Bishal K. Singh ◽  
Nandini Sarkar ◽  
M.V. Jagannadham ◽  
Vikash K. Dubey
Keyword(s):  
Leishmania Infantum ◽  
Trypanothione Reductase ◽  
Modeled Structure

scholarly journals Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives

2017 ◽  
Vol 32 (1) ◽  
pp. 304-310 ◽  
Author(s):  
Francesco Saccoliti ◽  
Gabriella Angiulli ◽  
Giovanni Pupo ◽  
Luca Pescatori ◽  
Valentina Noemi Madia ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Trypanothione Reductase ◽  
Diaryl Sulfide

scholarly journals Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

2016 ◽  
Vol 60 (6) ◽  
pp. 3802-3812 ◽  
Author(s):  
Ylenia Baquedano ◽  
Verónica Alcolea ◽  
Miguel Ángel Toro ◽  
Killian Jesús Gutiérrez ◽  
Paul Nguewa ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Inhibitory Activity ◽  
Leishmania Infantum ◽  
Trypanothione Reductase ◽  
Content Type ◽  
Bioactive Scaffolds ◽  
Lead Compounds ◽  
Novel Structures ◽  
Micromolar Range

A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and theirin vitroleishmanicidal activities againstLeishmania infantumamastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED50) values ranging from 0.45 to 1.27 μM and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3′-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.

Leishmania infantum trypanothione reductase is a promiscuous enzyme carrying an NADPH:O2 oxidoreductase activity shared by glutathione reductase

2015 ◽  
Vol 1850 (9) ◽  
pp. 1891-1897 ◽  
Author(s):  
Gabriella Angiulli ◽  
Antonella Lantella ◽  
Elena Forte ◽  
Francesco Angelucci ◽  
Gianni Colotti ◽  
...  
Keyword(s):  
Glutathione Reductase ◽  
Leishmania Infantum ◽  
Trypanothione Reductase ◽  
Oxidoreductase Activity

scholarly journals Footprinting of Inhibitor Interactions ofIn SilicoIdentified Inhibitors of Trypanothione Reductase ofLeishmaniaParasite

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Santhosh K. Venkatesan ◽  
Vikash Kumar Dubey
Keyword(s):  
Virtual Screening ◽  
Leishmania Infantum ◽  
Trypanothione Reductase ◽  
Inhibition Kinetics ◽  
Screening Process ◽  
Protein Ligand Interactions ◽  
Enzymatic Reduction ◽  
Ligand Interactions ◽  
First Time

Structure-based virtual screening of NCI Diversity set II compounds was performed to indentify novel inhibitor scaffolds of trypanothione reductase (TR) fromLeishmania infantum. The top 50 ranked hits were clustered using the AuPoSOM tool. Majority of the top-ranked compounds were Tricyclic. Clustering of hits yielded four major clusters each comprising varying number of subclusters differing in their mode of binding and orientation in the active site. Moreover, for the first time, we report selected alkaloids and dibenzothiazepines as inhibitors ofLeishmania infantumTR. The mode of binding observed among the clusters also potentiates the probablein vitroinhibition kinetics and aids in defining key interaction which might contribute to the inhibition of enzymatic reduction of T[S] 2. The method provides scope for automation and integration into the virtual screening process employing docking softwares, for clustering the small molecule inhibitors based upon protein-ligand interactions.

scholarly journals Inhibitory Effect of Silver Nanoparticles on Trypanothione Reductase Activity and Leishmania infantum Proliferation

2010 ◽  
Vol 2 (3) ◽  
pp. 230-233 ◽  
Author(s):  
Paola Baiocco ◽  
Andrea Ilari ◽  
Pierpaolo Ceci ◽  
Stefania Orsini ◽  
Marina Gramiccia ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Leishmania Infantum ◽  
Reductase Activity ◽  
Inhibitory Effect ◽  
Trypanothione Reductase

scholarly journals Epigallocathechin-O-3-Gallate Inhibits Trypanothione Reductase of Leishmania infantum, Causing Alterations in Redox Balance and Leading to Parasite Death

2021 ◽  
Vol 11 ◽  
Author(s):  
Job D. F. Inacio ◽  
Myslene S. Fonseca ◽  
Gabriel Limaverde-Sousa ◽  
Ana M. Tomas ◽  
Helena Castro ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Redox Homeostasis ◽  
Protozoan Parasite ◽  
Redox Balance ◽  
Competitive Inhibitor ◽  
Flavonoid Compound ◽  
Trypanothione Reductase ◽  
Dependent Manner ◽  
Concentration Dependent Manner

Leishmania infantum is a protozoan parasite that causes a vector borne infectious disease in humans known as visceral leishmaniasis (VL). This pathology, also caused by L. donovani, presently impacts the health of 500,000 people worldwide, and is treated with outdated anti-parasitic drugs that suffer from poor treatment regimens, severe side effects, high cost and/or emergence of resistant parasites. In previous works we have disclosed the anti-Leishmania activity of (-)-Epigallocatechin 3-O-gallate (EGCG), a flavonoid compound present in green tea leaves. To date, the mechanism of action of EGCG against Leishmania remains unknown. This work aims to shed new light into the leishmanicidal mode of action of EGCG. Towards this goal, we first confirmed that EGCG inhibits L. infantum promastigote proliferation in a concentration-dependent manner. Second, we established that the leishmanicidal effect of EGCG was associated with i) mitochondria depolarization and ii) decreased concentration of intracellular ATP, and iii) increased concentration of intracellular H2O2. Third, we found that the leishmanicidal effect and the elevated H2O2 levels induced by of EGCG can be abolished by PEG-catalase, strongly suggesting that this flavonoid kills L. infantum promastigotes by disturbing their intracellular redox balance. Finally, we gathered in silico and in vitro evidence that EGCG binds to trypanothione reductase (TR), a central enzyme of the redox homeostasis of Leishmania, acting as a competitive inhibitor of its trypanothione substrate.

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