The Experts below are selected from a list of 1635 Experts worldwide ranked by ideXlab platform
Alan H Fairlamb - One of the best experts on this subject based on the ideXlab platform.
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synthesis and evaluation of indatraline based inhibitors for Trypanothione Reductase
ChemMedChem, 2011Co-Authors: Jeffrey G A Walton, Deuan C Jones, Paula Kiuru, Alastair J Durie, Nicholas J Westwood, Alan H FairlambAbstract:The search for novel compounds of relevance to the treatment of diseases caused by trypanosomatid protozoan parasites continues. Screening of a large library of known bioactive compounds has led to several drug-like starting points for further optimisation. In this study, novel analogues of the monoamine uptake inhibitor indatraline were prepared and assessed both as inhibitors of Trypanothione Reductase (TryR) and against the parasite Trypanosoma brucei. Although it proved difficult to significantly increase the potency of the original compound as an inhibitor of TryR, some insight into the preferred substituent on the amine group and in the two aromatic rings of the parent indatraline was deduced. In addition, detailed mode of action studies indicated that two of the inhibitors exhibit a mixed mode of inhibition.
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investigation of Trypanothione Reductase as a drug target in trypanosoma brucei
ChemMedChem, 2009Co-Authors: Daniel Spinks, Alan H Fairlamb, Deuan C Jones, Emma Shanks, Laura A T Cleghorn, Stuart P Mcelroy, Daniel James, Julie A Frearson, Paul G Wyatt, Ian H GilbertAbstract:There is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human African trypanosomiasis, which is caused by Trypanosoma brucei. The enzyme Trypanothione Reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62 000 compound library against T. brucei TryR. Further work was undertaken to optimise potency and selectivity of two novel-compound series arising from the enzymatic and whole parasite screens and mammalian cell counterscreens. Both of these series, containing either a quinoline or pyrimidinopyrazine scaffold, yielded low micromolar inhibitors of the enzyme and growth of the parasite. The challenges of inhibiting TryR with druglike molecules is discussed.
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improved tricyclic inhibitors of Trypanothione Reductase by screening and chemical synthesis
ChemMedChem, 2009Co-Authors: John Richardson, Deuan C Jones, Ian H Gilbert, Isabelle R E Nett, Mohamed H Abdille, Alan H FairlambAbstract:Trypanothione Reductase (TryR) is a key validated enzyme in the Trypanothione-based redox metabolism of pathogenic trypanosomes and leishmania parasites. This system is absent in humans, being replaced with glutathione and glutathione Reductase, and as such offers a target for selective inhibition. As part of a program to discover antiparasitic drugs, the LOPAC1280 library of 1266 compounds was screened against TryR and the top hits evaluated against glutathione Reductase and T. brucei parasites. The top hits included a number of known tricyclic neuroleptic drugs along with other new scaffolds for TryR. Three novel druglike hits were identified and SAR studies on one of these using information from the tricyclic neuroleptic agents led to the discovery of a competitive inhibitor (Ki=330 nm) with an improved potency against T. brucei (EC50=775 nm).
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Trypanothione Reductase high throughput screening campaign identifies novel classes of inhibitors with antiparasitic activity
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Georgina A Holloway, Alan H Fairlamb, Reto Brun, Patrizia M Novello, John P Parisot, John Richardson, Marcel Kaiser, William N Charman, Edmund Kostewicz, Ian P StreetAbstract:High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of Trypanothione Reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening campaign.
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Inhibition of Trypanothione Reductase and glutathione Reductase by ferrocenic 4-aminoquinoline ureas
Arkivoc, 2008Co-Authors: Margaret A.l. Blackie, Alan H Fairlamb, Ahilan Saravanamuthu, Kelly ChibaleAbstract:New ferrocenic 4-aminoquinoline urea compounds have been tested for inhibition of Trypanothione Reductase (TryR) and human glutathione Reductase (GR). Several compounds were also tested in vitro against Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei rhodesiense. All compounds showed significant improvement in inhibition of TryR relative to chloroquine with the best compound showing an IC50 value of 2.4μM (Chloroquine IC50 = 47.6 μM).
Christian Sergheraert - One of the best experts on this subject based on the ideXlab platform.
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Trypanothione Reductase inhibition/trypanocidal activity relationships in a 1,4-bis(3-aminopropyl)piperazine series
Bioorganic & Medicinal Chemistry, 2000Co-Authors: Beatrice Bonnet, Valerie Landry, Elisabeth Davioud-charvet, David Soullez, Sophie Girault, Louis Jules Roger Marie Maes, Christian SergheraertAbstract:A series of symmetrically substituted 1,4-bis(3-aminopropyl)piperazines was synthesized and tested towards Trypanothione Reductase and for its in vitro trypanocidal potency. The most trypanocidal amongst them was found to be totally inactive towards the enzyme and thus constitutes a lead structure for the identification of new potential Trypanosoma cruzi target(s).
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Trypanothione Reductase inhibition trypanocidal activity relationships in a 1 4 bis 3 aminopropyl piperazine series
Bioorganic & Medicinal Chemistry, 2000Co-Authors: Beatrice Bonnet, Valerie Landry, Louis Maes, Elisabeth Davioudcharvet, David Soullez, Sophie Girault, Christian SergheraertAbstract:A series of symmetrically substituted 1,4-bis(3-aminopropyl)piperazines was synthesized and tested towards Trypanothione Reductase and for its in vitro trypanocidal potency. The most trypanocidal amongst them was found to be totally inactive towards the enzyme and thus constitutes a lead structure for the identification of new potential Trypanosoma cruzi target(s).
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a general approach to the synthesis of polyamine linked monoindolylmaleimides a new series of Trypanothione Reductase inhibitors
Chemical & Pharmaceutical Bulletin, 1998Co-Authors: Laurence Salmon, Christian Sergheraert, Valerie Landry, Oleg Melnyk, Louis Maes, Elisabeth DavioudcharvetAbstract:A simplified approach to the synthesis of 2-polyamine linked-monoindolylmaleimides has been achieved, leading to a new series of Trypanothione Reductase inhibitors. The conditions of access to N, 2-bis(polyamine)-3-monoindolylmaleimides and N, N'-bis(monoindolylmaleimide) polyamines are described. Measured inhibitory activities towards Trypanothione Reductase from Tryanosoma cruzi show the importance of both aromatic moieties and polyamine chains for Trypanothione Reductase recognition.
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New spermine and spermidine derivatives as potent inhibitors of Trypanosoma cruzi Trypanothione Reductase
Bioorganic & Medicinal Chemistry, 1997Co-Authors: Beatrice Bonnet, Valerie Landry, Elisabeth Davioud-charvet, David Soullez, Dragos Horvath, Christian SergheraertAbstract:Abstract Several spermine and spermidine derivatives containing 2-amino diphenylsulfide substituents were prepared and tested for their inhibiting effects on Trypanosoma cruzi Trypanothione Reductase. IC 50 values were assessed between 0.3 and 3 μM. Compound 32 ( K i = 0.4 μM) is the most potent TR inhibitor described so far.
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2-Amino diphenylsulfides as inhibitors of Trypanothione Reductase: modification of the side chain
Bioorganic & Medicinal Chemistry, 1996Co-Authors: Stéphanie Baillet, Beatrice Bonnet, Dragos Horvath, Louis Jules Roger Marie Maes, Eric Buisine, Christian SergheraertAbstract:Abstract A molecular modeling study meant to detect pharmacophore-like patterns in the active site of Trypanothione Reductase (TR) offered hints about the opportunity of synthesizing and testing diphenylsulfide derivatives with prolonged or branched polyamino side chains as putative TR inhibitors. The inhibition results within the synthesized series confirmed the main working hypothesis inspired by the molecular modeling study. The different compounds were tested in vitro on the enzyme and on Trypanosoma cruzi and Trypanosoma brucei trypomastigotes as well as in vivo in infected mice.
Mark Bradley - One of the best experts on this subject based on the ideXlab platform.
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mechanism and structure activity relationships of norspermidine based peptidic inhibitors of Trypanothione Reductase
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Mark J. Dixon, Jonathan W. Essex, Richard I Maurer, Cristina Biggi, Julen Oyarzabal, Mark BradleyAbstract:A library of polyamine-peptide conjugates based around some previously identified inhibitors of Trypanothione Reductase was synthesised by parallel solid-phase chemistry and screened. Kinetic analysis of library members established that subtle structural changes altered their mechanism of action, switching between competitive and non-competitive inhibition. The mode of action of the non-competitive inhibitors was investigated in detail by a variety of techniques including enzyme kinetic analysis (looking at both NADPH and Trypanothione disulfide substrates), gel filtration chromatography and analytical ultracentrifugation, leading to the identification of an allosteric mode of inhibition.
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Solid-phase synthesis of a focused library of Trypanothione Reductase inhibitors
Tetrahedron Letters, 2003Co-Authors: Stefania De Luca, Saraj Ulhaq, Mark J. Dixon, Jonathan W. Essex, Mark BradleyAbstract:A focused library of inhibitors of the enzyme Trypanothione Reductase was prepared using solid-phase synthesis. The inhibitors were based on a previously identified, non-competitive, lead compound comprising of two Pmc (2,2,5,7,8-pentamethylchroman-6-sulfonyl) side-chain protected, N-capped arginine residues linked by a spermidine bridge. In total six protecting groups and four capping groups were used to generate a 24-membered library. All compounds bearing the 5-methoxyindole-3-acetic acid capping group were found to have good activity. The most potent inhibitor was observed to contain the Mtr (4-methoxy-2,3,6-trimethylbenzenesulphonyl) protecting group on the arginine residue, terminated with tryptophan as the capping group.
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Solid phase synthesis of Trypanothione Reductase inhibitors—towards single bead screening
Tetrahedron Letters, 2001Co-Authors: David Orain, Mark BradleyAbstract:Using solid phase chemistry, inhibitors of Trypanothione Reductase were synthesised on TentaGel resin using a biologically compatible safety-catch linker. The material released was of high purity, while cleavage kinetics indicated the potential of the system for multiple release.
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optimising inhibitors of Trypanothione Reductase using solid phase chemistry
Bioorganic & Medicinal Chemistry Letters, 2000Co-Authors: Bordin Chitkul, Mark BradleyAbstract:Abstract A series of inhibitors of the enzyme Trypanothione Reductase has been identified using directed solid-phase chemistry. The compounds were based on a series of polyamine scaffolds and used the natural product kukoamine A as the lead structure. A compound with a K i of 76 nM was identified, although somewhat surprisingly the compound appeared to be noncompetitive in nature.
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Comparison of Resin and Solution Screening Methodologies in Combinatorial Chemistry and the Identification of a 100 nM Inhibitor of Trypanothione Reductase
ACS Combinatorial Science, 1999Co-Authors: Helen E. K. Smith, Mark BradleyAbstract:Two identical polyamine peptide conjugate libraries were screened against the parasitic enzyme Trypanothione Reductase. One of these libraries was in a solution format, while the other was resin-based and was used in two resin-based screens (a diminution assay and a direct bead screening). Potent inhibitors (100 nM) of Trypanothione Reductase were identified both in the solution screen and in the resin-based screens when using the PEGA resin of Meldal. Resin screening of both types failed to work with TentaGel resin. Importantly there was excellent agreement between the solution and resin-based assays, suggesting both methods are reliable for the screening of combinatorial libraries.
Elisabeth Davioudcharvet - One of the best experts on this subject based on the ideXlab platform.
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irreversible inactivation of Trypanothione Reductase by unsaturated mannich bases a divinyl ketone as key intermediate
Journal of Medicinal Chemistry, 2005Co-Authors: Holger Bauer, Elisabeth Davioudcharvet, Johannes Melchers, Thomas Ruppert, Lauren Rattray, R L KrauthsiegelAbstract:Trypanothione Reductase is a flavoenzyme unique to trypanosomatid parasites. Here we show that unsaturated Mannich bases irreversibly inactivate Trypanothione Reductase from Trypanosoma cruzi, the causative agent of Chagas' disease. The inhibitory potency of the compounds strongly increased upon storage of the DMSO stock solutions. HPLC, NMR, and mass spectrometry data of potential intermediates revealed a divinyl ketone as the active compound inactivating the enzyme. ESI- and MALDI-TOF mass spectrometry of Trypanothione Reductase modified by the Mannich base or the divinyl ketone showed specific alkylation of the active site Cys52 by a 5-(2'chlorophenyl)-3-oxo-4-pentenyl substituent. The reaction mechanism and the site of alkylation differ from those in Plasmodium falciparum thioredoxin Reductase where the C-terminal redox active dithiol is modified. After deamination, unsaturated Mannich bases are highly reactive in polycondensation with Trypanothione. Interaction of these compounds with both Trypanothione and Trypanothione Reductase could account for their potent trypanocidal effect against Trypanosoma brucei.
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Trypanothione Reductase inhibition trypanocidal activity relationships in a 1 4 bis 3 aminopropyl piperazine series
Bioorganic & Medicinal Chemistry, 2000Co-Authors: Beatrice Bonnet, Valerie Landry, Louis Maes, Elisabeth Davioudcharvet, David Soullez, Sophie Girault, Christian SergheraertAbstract:A series of symmetrically substituted 1,4-bis(3-aminopropyl)piperazines was synthesized and tested towards Trypanothione Reductase and for its in vitro trypanocidal potency. The most trypanocidal amongst them was found to be totally inactive towards the enzyme and thus constitutes a lead structure for the identification of new potential Trypanosoma cruzi target(s).
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structure activity relationships in 2 aminodiphenylsulfides against Trypanothione Reductase from trypanosoma cruzi
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: S Girault, Laurence Salmon, Elisabeth Davioudcharvet, Amaya Berecibar, Marieange Debreu, C SergheraertAbstract:Abstract In order to establish structural elements responsible for inhibition of Trypanothione Reductase (TR) from Trypanosoma cruzi by 2-aminodiphenylsulfides, a series of dissymmetrical derivatives, corresponding to the replacement of one aromatic moiety by different amines, was synthesized. TR inhibition studies revealed the importance of the aromatic rings and of the amino groups in the side chains for potent inhibition. Quinonic moities were also introduced with the aim of acting as TR redox-cycling substrates.
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a general approach to the synthesis of polyamine linked monoindolylmaleimides a new series of Trypanothione Reductase inhibitors
Chemical & Pharmaceutical Bulletin, 1998Co-Authors: Laurence Salmon, Christian Sergheraert, Valerie Landry, Oleg Melnyk, Louis Maes, Elisabeth DavioudcharvetAbstract:A simplified approach to the synthesis of 2-polyamine linked-monoindolylmaleimides has been achieved, leading to a new series of Trypanothione Reductase inhibitors. The conditions of access to N, 2-bis(polyamine)-3-monoindolylmaleimides and N, N'-bis(monoindolylmaleimide) polyamines are described. Measured inhibitory activities towards Trypanothione Reductase from Tryanosoma cruzi show the importance of both aromatic moieties and polyamine chains for Trypanothione Reductase recognition.
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new potent inhibitors of Trypanothione Reductase from trypanosoma cruzi in the 2 aminodiphenylsulfide series
European Journal of Medicinal Chemistry, 1997Co-Authors: S Girault, André Tartar, Elisabeth Davioudcharvet, Dragos Horvath, S Baillet, V Lucas, C SergheraertAbstract:Summary From a screening assay, 2-aminodiphenylsulfides were selected as leads for Trypanothione Reductase (TR) inhibition and studied by molecular modelling in the catalytic site of the enzyme. A series of analogues, monomers or bis-derivatives, were synthesized to improve binding energy and therefore inhibiting potency. These compounds appeared to be mixed competitive TR inhibitors and their inhibition profile could be explained when their aggregation in solution was taken into consideration. A bis-aminodiphenylsulfide with an IC 50 of 0.55 μM was revealed to be the best TR inhibitor described so far.
Beatrice Bonnet - One of the best experts on this subject based on the ideXlab platform.
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Trypanothione Reductase inhibition trypanocidal activity relationships in a 1 4 bis 3 aminopropyl piperazine series
Bioorganic & Medicinal Chemistry, 2000Co-Authors: Beatrice Bonnet, Valerie Landry, Louis Maes, Elisabeth Davioudcharvet, David Soullez, Sophie Girault, Christian SergheraertAbstract:A series of symmetrically substituted 1,4-bis(3-aminopropyl)piperazines was synthesized and tested towards Trypanothione Reductase and for its in vitro trypanocidal potency. The most trypanocidal amongst them was found to be totally inactive towards the enzyme and thus constitutes a lead structure for the identification of new potential Trypanosoma cruzi target(s).
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Trypanothione Reductase inhibition/trypanocidal activity relationships in a 1,4-bis(3-aminopropyl)piperazine series
Bioorganic & Medicinal Chemistry, 2000Co-Authors: Beatrice Bonnet, Valerie Landry, Elisabeth Davioud-charvet, David Soullez, Sophie Girault, Louis Jules Roger Marie Maes, Christian SergheraertAbstract:A series of symmetrically substituted 1,4-bis(3-aminopropyl)piperazines was synthesized and tested towards Trypanothione Reductase and for its in vitro trypanocidal potency. The most trypanocidal amongst them was found to be totally inactive towards the enzyme and thus constitutes a lead structure for the identification of new potential Trypanosoma cruzi target(s).
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New spermine and spermidine derivatives as potent inhibitors of Trypanosoma cruzi Trypanothione Reductase
Bioorganic & Medicinal Chemistry, 1997Co-Authors: Beatrice Bonnet, Valerie Landry, Elisabeth Davioud-charvet, David Soullez, Dragos Horvath, Christian SergheraertAbstract:Abstract Several spermine and spermidine derivatives containing 2-amino diphenylsulfide substituents were prepared and tested for their inhibiting effects on Trypanosoma cruzi Trypanothione Reductase. IC 50 values were assessed between 0.3 and 3 μM. Compound 32 ( K i = 0.4 μM) is the most potent TR inhibitor described so far.
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2-Amino diphenylsulfides as inhibitors of Trypanothione Reductase: modification of the side chain
Bioorganic & Medicinal Chemistry, 1996Co-Authors: Stéphanie Baillet, Beatrice Bonnet, Dragos Horvath, Louis Jules Roger Marie Maes, Eric Buisine, Christian SergheraertAbstract:Abstract A molecular modeling study meant to detect pharmacophore-like patterns in the active site of Trypanothione Reductase (TR) offered hints about the opportunity of synthesizing and testing diphenylsulfide derivatives with prolonged or branched polyamino side chains as putative TR inhibitors. The inhibition results within the synthesized series confirmed the main working hypothesis inspired by the molecular modeling study. The different compounds were tested in vitro on the enzyme and on Trypanosoma cruzi and Trypanosoma brucei trypomastigotes as well as in vivo in infected mice.
