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 to isosteric replacement strategy to design 44 analogs which were evaluated against T. brucei . 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 (CATL) and DPPH antioxidant activities. The lead compound () showed antioxidant capacity and the best activity against T. brucei (EC = 0.47 μM). Nevertheless, its toxicity should be improved. We also predicted the interactions of these compounds with CATL utilizing molecular dynamics. We demonstrate that the derivatives are more active than their analogues, and that the selenazole ring decreases -associated toxicity. Also, thio- and selenosemicarbazones are more potent against CATL than the cyclic derivatives. We conclude that CATL inhibition should be combined with antioxidant activity to obtain active compounds against T. brucei.