Quinuclidine derivatives as potential antiparasitics

Simon B. Cammerer, Carmen Jimenez, Simon Jones, Ludovic Gros, Silvia Orenes Lorente, Carlos Rodrigues, Juliany C. F. Rodrigues, Aura Caldera, Luis Miguel Ruiz Perez, Wanderley da Souza, Marcel Kaiser, Reto Brun, Julio A. Urbina, Dolores Gonzalez Pacanowska, Ian H. Gilbert

    Research output: Contribution to journalArticlepeer-review

    34 Citations (Scopus)

    Abstract

    There is an urgent need for the development of new drugs for the treatment of tropical parasitic diseases such as Chagas' disease and leishmaniasis. One potential drug target in the organisms that cause these diseases is sterol biosynthesis. This paper describes the design and synthesis of quinuclidine derivatives as potential inhibitors of a key enzyme in sterol biosynthesis, squalene synthase (SQS). A number of compounds that were inhibitors of the recombinant Leishmania major SQS at submicromolar concentrations were discovered. Some of these compounds were also selective for the parasite enzyme rather than the homologous human enzyme. The compounds inhibited the growth of and sterol biosynthesis in Leishmania parasites. In addition, we identified other quinuclidine derivatives that inhibit the growth of Trypanosoma brucei (the causative organism of human African trypanosomiasis) and Plasmodium falciparum (a causative agent of malaria), but through an unknown mode(s) of action.

    Original languageEnglish
    Pages (from-to)4049-4061
    Number of pages13
    JournalAntimicrobial Agents and Chemotherapy
    Volume51
    Issue number11
    DOIs
    Publication statusPublished - Nov 2007

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