Because of the high incidence of malaria and cancer in many parts of the world, effective and safe new chemotherapies of these human diseases are urgently needed. Toward developing such practical new chemotherapeutic drugs, we are blending chemical insight and synthesis skills with biological testing initially in vitro and then in vivo to establish efficacy and safety. This blending of fundamental chemistry and pharmacology research with practical pre-clinical development of new drugs candidates highlights our ongoing research program at Hopkins on trioxanes for chemotherapy of malaria and cancer. Based on the fundamental new knowledge we have generated about the molecular mechanism of action of potent anti-infective peroxides like the natural trioxane artemisinin, we propose the following, five diverse research goals for the next five years: (1) to design, prepare and evaluate structurally simple, inexpensive, potent, and safe next-generation antimalarial trioxanes; (2) to design, prepare and evaluate dimetric peroxides as new anti-infective and especially antitumor drug candidates; (4) to invent new synthetic methods for efficiently and inexpensive constructing chemotherapeutic antimalarial peroxides; (5) to design, prepare and evaluate new antimalarial endoperoxide analogs in which the peroxide groups is replaced by other heteroatoms. As medicinal chemists, we are a unique position to make fundamental advances in molecular parasitology specifically concerning mechanism of action and unproved therapeutic aspects of easily prepared and relatively inexpensive new endoperoxide antimalarial and antitumor drugs.
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