Betraying the Parasite’s Redox System: Diaryl Sulfide-Based Inhibitors of Trypanothione Reductase: Subversive Substrates and Antitrypanosomal Properties

ChemMedChem ◽  
2007 ◽  
Vol 2 (12) ◽  
pp. 1708-1712 ◽  
Author(s):  
Bernhard Stump ◽  
Marcel Kaiser ◽  
Reto Brun ◽  
R. Luise Krauth-Siegel ◽  
François Diederich
Keyword(s):  
Redox System ◽  
Trypanothione Reductase ◽  
Diaryl Sulfide

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 Ebsulfur Is a Benzisothiazolone Cytocidal Inhibitor Targeting the Trypanothione Reductase of Trypanosoma brucei

2013 ◽  
Vol 288 (38) ◽  
pp. 27456-27468 ◽  
Author(s):  
Jun Lu ◽  
Suman K. Vodnala ◽  
Anna-Lena Gustavsson ◽  
Tomas N. Gustafsson ◽  
Birger Sjöberg ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Trypanosoma Brucei ◽  
Mammalian Cells ◽  
Reactive Oxygen ◽  
Redox System ◽  
Trypanothione Reductase ◽  
Oxygen Species ◽  
African Trypanosomiasis ◽  
Thiol Redox

Trypanosoma brucei is the causing agent of African trypanosomiasis. These parasites possess a unique thiol redox system required for DNA synthesis and defense against oxidative stress. It includes trypanothione and trypanothione reductase (TryR) instead of the thioredoxin and glutaredoxin systems of mammalian hosts. Here, we show that the benzisothiazolone compound ebsulfur (EbS), a sulfur analogue of ebselen, is a potent inhibitor of T. brucei growth with a favorable selectivity index over mammalian cells. EbS inhibited the TryR activity and decreased non-protein thiol levels in cultured parasites. The inhibition of TryR by EbS was irreversible and NADPH-dependent. EbS formed a complex with TryR and caused oxidation and inactivation of the enzyme. EbS was more toxic for T. brucei than for Trypanosoma cruzi, probably due to lower levels of TryR and trypanothione in T. brucei. Furthermore, inhibition of TryR produced high intracellular reactive oxygen species. Hydrogen peroxide, known to be constitutively high in T. brucei, enhanced the EbS inhibition of TryR. The elevation of reactive oxygen species production in parasites caused by EbS induced a programmed cell death. Soluble EbS analogues were synthesized and cured T. brucei brucei infection in mice when used together with nifurtimox. Altogether, EbS and EbS analogues disrupt the trypanothione system, hampering the defense against oxidative stress. Thus, EbS is a promising lead for development of drugs against African trypanosomiasis.

Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine-Conjugated Diaryl Sulfide Scaffolds

ChemMedChem ◽  
2009 ◽  
Vol 4 (12) ◽  
pp. 2034-2044 ◽  
Author(s):  
Christian Eberle ◽  
Johannes A. Burkhard ◽  
Bernhard Stump ◽  
Marcel Kaiser ◽  
Reto Brun ◽  
...  
Keyword(s):  
Binding Mode ◽  
Trypanothione Reductase ◽  
Synthesis Inhibition ◽  
Inhibition Potency ◽  
Diaryl Sulfide

Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities

2008 ◽  
Vol 6 (21) ◽  
pp. 3935 ◽  
Author(s):  
Bernhard Stump ◽  
Christian Eberle ◽  
Marcel Kaiser ◽  
Reto Brun ◽  
R. Luise Krauth-Siegel ◽  
...  
Keyword(s):  
Binding Mode ◽  
Trypanothione Reductase ◽  
Inhibition Potency ◽  
Diaryl Sulfide

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.

Nonisochoric Reactor with Constant Feed Rate of One Component

1993 ◽  
Vol 58 (7) ◽  
pp. 1476-1484
Author(s):  
Václav Dušek ◽  
František Skopal
Keyword(s):  
Sulfuric Acid ◽  
Acid Medium ◽  
Feed Rate ◽  
Redox System ◽  
Chemical Reactor ◽  
Constant Volume ◽  
Rate Equations ◽  
Sulfuric Acid Medium ◽  
Constant Feed Rate

For a chemical reactor with constant volume feed rate equations have been derived which describe the time dependences of concentration of the reaction components, and their approximation has been suggested. The applicability of the approximation has been verified on a model redox system Ce(IV)/V(IV) in sulfuric acid medium.

Sign in / Sign up

Export Citation Format

Share Document