Optimising inhibitors of Trypanothione reductase using solid-phase chemistry

Chitkul, Bordin; Bradley, Mark

doi:10.1016/s0960-894x(00)00471-6

Cited by 36 publications

(25 citation statements)

References 6 publications

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“…Another example of suboptimal library design is the polyamine library ( Fig. 9.4) [8]. Polyamines, norspermidine, spermidine, and spermine were immobilized on solid support attached through an acid-cleavable linker using an efficient multistep protocol.…”

Section: Design Considerationsmentioning

confidence: 99%

Role of Chemistry in Lead Discovery

Dolle

Worm

2010

Lead Generation Approaches in Drug Discovery

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Section: Design Considerationsmentioning

confidence: 99%

Role of Chemistry in Lead Discovery

Dolle

Worm

2010

Lead Generation Approaches in Drug Discovery

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“…Screening a library of polyaminepeptide conjugates revealed several highly efficient non-competitive inhibitors with compound 11 giving a K i value of 100 nM (Smith and Bradley 1999). Starting with the natural product kukoamine A as lead structure, compound 12 with a K i value of 76 nM was obtained by solid-phase chemistry (Chitkul and Bradley 2000). The latter two compounds are the most potent reversible inhibitors of TR to date.…”

Section: Non-competitive Inhibitorsmentioning

confidence: 99%

Parasite-specific trypanothione reductase as a drug target molecule

Krauth‐Siegel

Inhoff

2003

Parasitol Res

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Trypanosomatids are the causative agents of African sleeping sickness, Chagas' disease, and the different manifestations of leishmaniasis. New drugs against these parasitic protozoa are urgently needed since the current drugs are unsatisfactory, in particular due to serious adverse side effects. In trypanosomes and leishmanias, the nearly ubiquitous glutathione/glutathione reductase system is replaced by trypanothione and trypanothione reductase. The essential role of trypanothione reductase in the parasite thiol metabolism and its absence from the mammalian host render the enzyme a highly attractive target molecule for a structure-based drug development against trypanosomatids. This article provides an overview on the known classes of trypanothione reductase inhibitors and their in vitro activity against parasitic protozoa. The (dis)advantages of the different types of compounds as potential drug candidates as well as modern computer-based approaches to the identification of new leads are discussed.

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“…IC 50 values against Trypanosoma brucei ranged from 0.12 µM to 0.27 µM for the tri-and tetra-substituted compounds. A similar rationale led to the synthesis of a series of inhibitors based on spermine and spermidine as polyamine scaffolds by solid-phase chemistry (18). These compounds were noncompetitive inhibitors of TR, with trypanothione as the variable substrate, and K i values were mostly less than 1 µM, with N 1 ,N 12 -bis(5-bromo-3-indoleacetyl)spermidine the most effective at 76 nM.…”

Section: Inhibitors Of Trypanothione Metabolismmentioning

confidence: 99%