Synthesis and testing of inhibitors of trypanothione reductase

CHED 879

Josephine Czechowicz and David G. Alberg. Department of Chemistry, Carleton College, 300 North College Street, Northfield, MN 55057
Unicellular parasites of genera Trypanosoma and Leishmania cause a number of diseases including African sleeping sickness and Chagas. Recent research has identified a metabolic pathway exclusive to these parasites—a promising target for development of new treatments. Central to this pathway is Trypanothione Reductase(TR), an NADPH- dependant flavin-enzyme responsible for the reduction of trypanothione from its disulfide to its dithiol form. These organisms rely heavily upon reduced trypanothione as a protector against deadly oxidative stress. In host organisms, Glutathione Reductase(GR) and glutathione, which the parasites lack, play an analogous role in the maintenance of a redox balance. Though TR and GR share similar functions, both display high specificity for their respective substrates. It is possible to inhibit TR in the parasite, inducing death by oxidative-stress, without also inhibiting GR in the host. Here I present my syntheses of two competitive TR inhibitors and my results from assays of their kinetic parameters.