Design and synthesis of novel antimalarial and anticancer artemisinin-derived trioxanes and thiol-olefin co-oxygenation (toco)-derived endoperoxides.

摘要

Endemic in over 100 countries, malaria continues to be the world's most deadly parasitic disease. With still over a million deaths each year, current advances in chemotherapy are imperative. The discovery of the active component of the Artemisia plant, known as artemisinin, is perhaps the most significant advance in malaria therapy in the last century. Artemisinin, first described in detail in the late 1970s, is incredibly potent against all strains of malaria but suffers from low water solubility, short plasma half-life, high cost, and potential for neurotoxicity.Based on previously developed dimers, several new series of potent, water-soluble, and non-toxic dimers of artemisinin have been developed. Of particular interest is the class of sulfone containing dimers, which had curative results when tested in vivo against malaria causing strains of Plasmodium. Additionally, this class of sulfone dimers was shown to be highly active in a range of anticancer screens. These dimers are hydrolytically stable and thermally stable indefinitely up to 60°C. In combination therapy with clinically-used mefloquine, these sulfone dimers cured malaria-infected mice in a single oral dose. This series of sulfone-containing dimers is being studied in comparison with analogous monomers of artemisinin. As of the date of this thesis, these tests were ongoing and preliminary data suggest the dimer is more potent in vivo than the analogous monomers at the same concentration. The development of a new, highly potent, low-cost artemisinin-based therapy is critical to fight and eventually eradicate malaria.