Chalcogen Derivatives for the Treatment of African Trypanosomiasis: Biological Evaluation of Thio- and Seleno-Semicarbazones and Their Azole Derivatives.

Human African trypanosomiasis (HAT) is caused by Trypanosoma brucei. Drug therapy remains challenging due to drug resistance and/or toxicity. New drugs are needed. Using thiosemicarbazones as a starting point, we employed a S to Se isosteric replacement strategy to design 44 analogs which were evaluated against T. brucei in vitro. Compounds were divided into 11 groups of four derivatives corresponding to thio-, selenosemicarbazones, and their cyclic counterparts, thio- and selenazoles. We selected three groups which contained a total of six derivatives that inhibited parasite growth by >70%. Then, we investigated the mechanism of action of these compounds, performing quantitative assays to measure their inhibition of the T. brucei cathepsin L-like protease (TbrCATL) and DPPH antioxidant activities. The lead compound (SeO3) showed antioxidant capacity and the best activity against T. brucei (EC(50) = 0.47 μM). Nevertheless, its toxicity should be improved. We also predicted the interactions of these compounds with TbrCATL utilizing molecular dynamics. We demonstrate that the Se derivatives are more active than their S analogues, and that the selenazole ring decreases Se-associated toxicity. Also, thio- and selenosemicarbazones are more potent against TbrCATL than the cyclic derivatives. We conclude that TbrCATL inhibition should be combined with antioxidant activity to obtain active compounds against T. brucei.