Synthesis and Investigation of the Pharmaceutical Properties of Drug Targets Against the Human African Trypanosomiasis (HAT)

Human African Trypanosomiasis (HAT), also known as African sleeping sickness, affects 50,000-70,000 people worldwide. The disease is most widespread in the sub-Saharan Africa. The parasitic species Trypanosoma brucei is spread by the Tsetse fly that transfers it into the host’s bloodstream upon biting. The disease agents are two sub-species of the parasite: T.b. rhodesiense and T.b. gambiense. The disease proceeds in two stages: hemolytic and neurological. The second stage occurs after the parasites cross the blood-brain barrier and is characterized by disorganized sleep cycle, confusion, paralysis, mood changes, coma, and eventually death. The drugs currently used to treat the disease are very toxic, difficult to administer, and are showing drug resistance. Our goal was a partial structure-activity study on two lead diphenyl ether compounds which show selectivity indices around 800 against the human cell lines. We altered the benzyl amine portion of the morpholine lead and carried out synthesis of the chloro derivative of the ethanoate lead. We have shown that chlorination in the morpholine series increases activity and that cyano substituents are much less active than benzyl amines. Our morpholine lead has better in vitro selectivity index, lower toxicity, and only slightly lower activity than the anti-HAT drug Eflornithine