Marine endoperoxides as antiprotozoan lead compounds

Chemical analysis of Caribbean and Indonesian marine sponges yielded a family of endoperoxide polyketides, some of which showed remarkable activity against protozoans responsible either of malaria or of African trypanosomiasis. For example, we have found that plakortin (1) is a potent antimalarial lead, while manadoperoxide B (2) is an ultrapotent antitrypanosomal agent (IC₅₀=8 nM). Resulting structure-activity relationships have been analyzed by means of experimental and computational techniques, thus gathering valuable insights into the mechanism of action of this class of compounds and information to guide the design of optimized antiprotozoan agents based on the dioxane scaffold. In this communication we will also illustrate a simple and versatile scheme of synthesis which, utilizing cheap and commercially available starting materials, afforded several structurally and stereochemically different compounds characterized by a 3-methoxy-1,2-dioxane scaffold.