Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the Leishmaniases

Lindsay B. Tulloch, Viviane P. Martini, Jorge Iulek, Judith K. Huggan, Jeong Hwan Lee, Colin L. Gibson, Terry K. Smith, Colin J. Suckling, William N. Hunter (Lead / Corresponding author)

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    47 Citations (Scopus)

    Abstract

    Pteridine reductase (PTR1) is a target for drug development against Trypanosoma and Leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. We adopted a structure-based approach to the design of novel PTR1 inhibitors based on three molecular scaffolds. A series of compounds, most newly synthesized, were identified as inhibitors with PTR1-species specific properties explained by structural differences between the T. brucei and L. major enzymes. The most potent inhibitors target T. brucei PTR1, and two compounds displayed antiparasite activity against the bloodstream form of the parasite. PTR1 contributes to antifolate drug resistance by providing a molecular bypass of dihydrofolate reductase (DHFR) inhibition. Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic effect was observed for one particular combination highlighting the potential of such an approach for treatment of African sleeping sickness.

    Original languageEnglish
    Pages (from-to)221-229
    Number of pages9
    JournalJournal of Medicinal Chemistry
    Volume53
    Issue number1
    DOIs
    Publication statusPublished - 14 Jan 2010

    Keywords

    • DIHYDROFOLATE-REDUCTASE
    • TRYPANOSOMA-BRUCEI
    • METABOLISM
    • TETRAHYDROBIOPTERIN
    • METHOTREXATE
    • RESISTANCE
    • BINDING
    • DIFFRACTION
    • GROWTH
    • ENZYME

    Cite this

    Tulloch, L. B., Martini, V. P., Iulek, J., Huggan, J. K., Lee, J. H., Gibson, C. L., Smith, T. K., Suckling, C. J., & Hunter, W. N. (2010). Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the Leishmaniases. Journal of Medicinal Chemistry, 53(1), 221-229. https://doi.org/10.1021/jm901059x