MALARIA CHEMOTHERAPY AND CHEMOPROTECTION

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Among infectious diseases, malaria is common in many parts of the world. Standard alkaloids such as quinine and chloroquine are becoming less and less effective because malaria parasites are developing resistance to such drugs. There is a critical and urgent need, therefore, for development of antimalarial vaccines and new antimalarial non-alkloidal drugs to treat this increasingly widespread international health problem. Ancient Chinese folk medicine has led relatively recently to discovery of sesquiterpene 1,2,4-trixane artemisnin (qinghaosu) representing a new class of non- alkaloidal, clinically useful antimalarial drugs. Although this trioxane antimalaria and its first-generation derivatives have many desirable features (e.g. fast action against even cerebral malaria, useful in combination chemotherapy with standard alkoloidal antimalarials like mefloguine), they have also some disadvantage (e.g. frequent recrudescendences when used alone, short half-lives). Therefore, design and synthesis of the next generation of simpler, inexpensive and therapeutically more desirable peroxide-containing antimalarials is appropriate. Based on the fundamental new knowledge we have generated about the various chemical intermediates involved in the molecular mechanism of action of potent antimalarial peroxides like artemisinin, we now propose the following research goals: (1) to design prepare and evaluate new mechanism-based antimalarial peroxides; (2) to design, prepare and evaluate structurally simple, inexpensive, potent, third-generation peroxidic antimalarials incorporating pharmacologically advantageous substituents and therefore having good chemotherapeutic properties; (3) to design, prepare and evaluate dimeric peroxides as new anti-infective and antitumor drugs; (4)as models for hemin-trixane adducts, to prepare amino acid adducts with the putative alkylating agents (e.g. epoxides, diketones) formed during ferrous ion activation of artemisnin and related antimalarial peroxides; (5) to design, prepare and evaluate new gametocytocidal peroxides for breaking the cycle of malaria transmission from man to mosquito (i.e. chemoprevention of malaria). A medicicinal chemists, we are in a unique position to make fundamental advances in molecular parasitology specifically concerning mechanism of action and improved therapeutic aspect of easily prepared and relatively inexpensive new endoperoxide antimalarial drugs.