Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal-antiplasmodial activity

Irene Sola, Sílvia Castellà, Elisabet Viayna, Carles Galdeano, Martin C. Taylor, Stephen Y. Gbedema, Belén Pérez, M. Victòria Clos, Deuan C. Jones, Alan H. Fairlamb, Colin W. Wright, John M. Kelly, Diego Muñoz-Torrero (Lead / Corresponding author)

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    12 Citations (Scopus)

    Abstract

    Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.

    Original languageEnglish
    Pages (from-to)5156-5167
    Number of pages12
    JournalBioorganic & Medicinal Chemistry
    Volume23
    Issue number16
    Early online date24 Jan 2015
    DOIs
    Publication statusPublished - 15 Aug 2015

    Keywords

    • Antimalarial agents
    • Brain permeability
    • Inhibitors of β-haematin formation
    • Molecular hybridization
    • Trypanocidal agents
    • Trypanothione reductase inhibitors

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  • Cite this

    Sola, I., Castellà, S., Viayna, E., Galdeano, C., Taylor, M. C., Gbedema, S. Y., Pérez, B., Clos, M. V., Jones, D. C., Fairlamb, A. H., Wright, C. W., Kelly, J. M., & Muñoz-Torrero, D. (2015). Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal-antiplasmodial activity. Bioorganic & Medicinal Chemistry, 23(16), 5156-5167. https://doi.org/10.1016/j.bmc.2015.01.031