Doctor of Philosophy, The Ohio State University, 2012, Pharmacy

Human African trypanosomiasis (HAT) and leishmaniasis are identified by the World Health Organization (WHO) as neglected tropical diseases (NTDs), together with Chagas disease and Buruli ulcer. These NTDs mostly affect people in remote or rural area, and there are very limited control and therapeutic options. The investment on research and development against NTDs is insufficient. Human African trypanosomiasis (HAT) is a vector-borne parasitic disease caused by Trypanosoma brucei subspecies. Transmitted by the tsetse fly, the disease mainly affects rural populations in sub-Saharan Africa and is fatal if untreated. New drugs are needed against HAT that are safe, affordable, easy to administer, active against first and second stage disease, and effective against both subspecies of T. brucei. From medicinal chemistry investigation in Karl Werbovetz group, several N1-substituted 1,2-dihydroquinoline-6-ols were discovered displaying nanomolar IC50 values in vitro against T. b. rhodesiense and selectivity indexes (SI) up to >18,000. OSU-40 (1-benzyl-1,2-dihydro-2,2,4–trimethylquinolin-6-yl acetate) is selectively potent against T. b. rhodesiense in vitro (IC50 = 14 nM, selectivity index = 1700), and has been proposed to cause the formation of reactive oxygen species (ROS) in African trypanosomes. In the present study, we sought to provide further support for the hypothesis that OSU-40 kills trypanosomes through oxidative stress. Inducible RNAi interference (RNAi) was applied to down-regulate key enzymes in parasite antioxidant defense, including trypanothione synthetase (TbTryS) and a superoxide dismutase (TbSODB). Both TbTryS RNAi-induced and TbSODB RNAi-induced cells showed impaired growth and increased sensitivity towards OSU-40 by 2.4-fold and 3.4-fold respectively. Decreased expression of key parasite antioxidant enzymes was thus associated with an increased sensitivity to OSU-40, consistent with the hypothesis that OSU-40 acts through oxidative stress. Finally, th (open full item for complete abstract)

Committee: Karl Werbovetz PhD (Advisor); Mark Drew PhD (Committee Member); Werner Tjarks PhD (Committee Member); Juan Alfonzo PhD (Committee Member) Subjects: Parasitology; Pharmacy Sciences