Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes

Andrea Taladriz, Alan Healy, Eddysson J. Flores Pérez, Vanessa Herrero García, Carlos Ríos Martínez, Abdulsalam A.M. Alkhaldi, Anthonius A. Eze, Marcel Kaiser, Harry P. De Koning, Antonio Chana, Christophe Dardonville

    Research output: Contribution to journalArticle

    Abstract

    A series of 73 bisphosphonium salts and 10 monophosphonium salt derivatives were synthesized and tested in vitro against several wild type and resistant lines of Trypanosoma brucei (T. b. rhodesiense STIB900, T. b. brucei strain 427, TbAT1-KO, and TbB48). More than half of the compounds tested showed a submicromolar EC 50 against these parasites. The compounds did not display any cross-resistance to existing diamidine therapies, such as pentamidine. In most cases, the compounds displayed a good selectivity index versus human cell lines. None of the known T. b. brucei drug transporters were required for trypanocidal activity, although some of the bisphosphonium compounds inhibited the low affinity pentamidine transporter. It was found that phosphonium drugs act slowly to clear a trypanosome population but that only a short exposure time is needed for irreversible damage to the cells. A comparative molecular field analysis model (CoMFA) was generated to gain insights into the SAR of this class of compounds, identifying key features for trypanocidal activity.

    Original languageEnglish (US)
    Pages (from-to)2606-2622
    Number of pages17
    JournalJournal of Medicinal Chemistry
    Volume55
    Issue number6
    DOIs
    StatePublished - Mar 22 2012

    Fingerprint

    Pentamidine
    Trypanosomiasis
    Salts
    Trypanosoma brucei brucei
    Pharmaceutical Preparations
    Parasites
    Cell Line
    Population
    Therapeutics

    ASJC Scopus subject areas

    • Molecular Medicine
    • Drug Discovery

    Cite this

    Taladriz, A., Healy, A., Flores Pérez, E. J., Herrero García, V., Ríos Martínez, C., Alkhaldi, A. A. M., ... Dardonville, C. (2012). Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes. Journal of Medicinal Chemistry, 55(6), 2606-2622. https://doi.org/10.1021/jm2014259

    Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes. / Taladriz, Andrea; Healy, Alan; Flores Pérez, Eddysson J.; Herrero García, Vanessa; Ríos Martínez, Carlos; Alkhaldi, Abdulsalam A.M.; Eze, Anthonius A.; Kaiser, Marcel; De Koning, Harry P.; Chana, Antonio; Dardonville, Christophe.

    In: Journal of Medicinal Chemistry, Vol. 55, No. 6, 22.03.2012, p. 2606-2622.

    Research output: Contribution to journalArticle

    Taladriz, A, Healy, A, Flores Pérez, EJ, Herrero García, V, Ríos Martínez, C, Alkhaldi, AAM, Eze, AA, Kaiser, M, De Koning, HP, Chana, A & Dardonville, C 2012, 'Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes', Journal of Medicinal Chemistry, vol. 55, no. 6, pp. 2606-2622. https://doi.org/10.1021/jm2014259
    Taladriz A, Healy A, Flores Pérez EJ, Herrero García V, Ríos Martínez C, Alkhaldi AAM et al. Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes. Journal of Medicinal Chemistry. 2012 Mar 22;55(6):2606-2622. https://doi.org/10.1021/jm2014259
    Taladriz, Andrea ; Healy, Alan ; Flores Pérez, Eddysson J. ; Herrero García, Vanessa ; Ríos Martínez, Carlos ; Alkhaldi, Abdulsalam A.M. ; Eze, Anthonius A. ; Kaiser, Marcel ; De Koning, Harry P. ; Chana, Antonio ; Dardonville, Christophe. / Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 6. pp. 2606-2622.
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