Targeting a Large Active Site: Structure‐Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase

Trypanothione reductase (TR) plays a key role in the unique redox metabolism of trypanosomatids, the causative agents of human African trypanosomiasis (HAT), Chagas’ disease, and leishmaniases. Introduction of a new, lean propargylic vector to a known class of TR inhibitors resulted in the strongest reported competitive inhibitor of Trypanosoma ( T .) brucei TR, with an inhibition constant K i of 73 n m , which is fully selective against human glutathione reductase (hGR). The best ligands exhibited in vitro IC 50 values (half‐maximal inhibitory concentration) against the HAT pathogen, T. brucei rhodesiense , in the mid‐nanomolar range, reaching down to 50 n m. X‐Ray co‐crystal structures confirmed the binding mode of the ligands and revealed the presence of a HEPES buffer molecule in the large active site. Extension of the propargylic vector, guided by structure‐based design, to replace the HEPES buffer molecule should give inhibitors with low nanomolar K i and IC 50 values for in vivo studies.