Quinuclidine Derivatives as Potential Antiparasitics

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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 recombinantLeishmania majorSQS 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 inLeishmaniaparasites. In addition, we identified other quinuclidine derivatives that inhibit the growth ofTrypanosoma brucei(the causative organism of human African trypanosomiasis) andPlasmodium falciparum(a causative agent of malaria), but through an unknown mode(s) of action.