Inhibition of the enzyme trypanothione reductase (TR) has proved to be effective against the parasite Trypanosoma brucei, which causes the african sleeping sickness. Causative agents of chagas disease and leishmaniasis, namely Trypanosoma cruzi and Leishmania donovani, also possess this enzyme and, therefore, represent potential targets of TR inhibitors. In 2014, we reported the biological evaluation and the first co-crystal structures showing the binding mode of small TR inhibitors derived from BTCP (1-[1-(benzo[b]thien-2-yl)cyclohexyl]piperidine), previously reported to be a low-molecular-weight inhibitor of TR by Fairlamb and co-workers. The information about the binding mode of these inhibitors laid the foundation for the rational structure-based design of small molecules to be bound in the large solvent exposed active site of TR. Some of the reported analogues exhibited poor water solubility, which severely impeded their biological evaluation and co-crystallization. We have now developed other, promising derivatives with better water solubility and a 3-fold increase in binding affinity (Kic = 3.9 ± 0.3 μM) for Trypanosoma brucei TR. Newly obtained co-crystal structures confirmed our previously reported binding mode for these derivatives in the large active site of TR.

Addressing a large active site: Inhibition of trypanothione reductase with cyclohexylpyrrolidine-based ligands

254th National Meeting (2017)

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