Improved Tricyclic Inhibitors of Trypanothione Reductase by Screening and Chemical Synthesis

John L. Richardson, Isabelle R. E. Nett, Deuan C. Jones, Mohamed H. Abdille, Ian H. Gilbert, Alan H. Fairlamb

    Research output: Contribution to journalArticlepeer-review

    56 Citations (Scopus)

    Abstract

    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 K-i=330 nM) with an improved potency against T. brucei (EC50 = 775 nM).

    Original languageEnglish
    Pages (from-to)1333-1340
    Number of pages8
    JournalChemMedChem
    Volume4
    Issue number8
    DOIs
    Publication statusPublished - Aug 2009

    Keywords

    • drug discovery
    • inhibitors
    • oxidoreductases
    • trypanosoma brucei
    • trypanothione reductase
    • BLOOD-STREAM FORMS
    • TRYPANOSOMA-CRUZI
    • GLUTATHIONE-REDUCTASE
    • LEISHMANIA-DONOVANI
    • ANTITRYPANOSOMAL ACTIVITY
    • COMPETITIVE INHIBITORS
    • CRITHIDIA-FASCICULATA
    • SUBSTRATE-SPECIFICITY
    • POLYAMINE DERIVATIVES
    • AFRICAN TRYPANOSOMES

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