In this article, the design and synthesis of some novel azasterols is described, followed by their evaluation against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum, the causative agents of human African trypanosomiasis, Chagas disease, leishmaniasis, and malaria, respectively. Some of the compounds showed anti-parasitic activity. In particular, a number of compounds appeared to very potently inhibit the growth of the blood stream form T. b. rhodesiense, with one compound giving an IC50 value of 12 nM. Clear structure activity relationships could be discerned. These compounds represent important leads for further optimization. Azasterols have previously been shown to inhibit sterol biosynthesis in T. cruzi and L. donovani by the inhibition of the enzyme sterol 24-methyltransferase. However, in this case, none of the compounds showed inhibition of the enzyme. Therefore, these compounds have an unknown mode of action.

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.Leishmaniasis and Chagas' disease are parasitic diseases caused by the protozoan parasites Leishmania spp. and Trypanosoma cruzi, respectively. Together, both diseases are responsible for high rates of mortality and morbidity, especially in tropical regions of the world. With increasing problems due to resistance and clinical efficacy, the drugs currently used to treat these diseases are becoming increasingly less effective, resulting in the urgent need for new drug candidates in this area.A particular area of interest are the enzymes of the sterol biosynthesis pathway; these provide attractive targets because the parasites that cause these diseases have ergosterol and other 24-alkylated sterols as the principal sterols present in the plasma membrane, while humans have cholesterol. Encouragingly, a number of enzymes in the sterol biosynthetic pathway have been studied as potential drug targets in these organisms and have shown great promise. Thus, 14␣-demethylase (9, 17-20, 29, 30, 38, 41, 42, 45), sterol 24-methyltransferase (9, 20-24, 32, 44, 46, 48), 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase (8, 40), squalene epoxidase (18, 39), squalene synthase (SQS) (7,31,33,36,37), and farnesyl pyrophosphate synthase (25-27, 50) have been studied both individually and in combination, with various degrees of success.The enzyme SQS, which catalyzes the condensation of two molecules of farnesyl pyrophosphate to produce squalene, has been identified as a potential drug target for the inhibition of cholesterol biosynthesis in humans (5). The activities of a variety of compounds, including bisphosphonates, benzylamines, squalestatins, and quinuclidines, against mammalian enzymes have been investigated. One class of compounds whose activities against mammalian SQS have been studied extensively are the arylquinuclidines. These compounds are protonated at physiological pH and are thought to mimic a high-energy carbocation intermediate in the reaction pathway. We are interested in this class of molecules and recently demonstrated that 3-biphenyl-4-y...