Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities

Abstract

Trypanothione reductase (TR) is an essential enzyme of trypanosomatids and therefore a promising target for the development of new drugs against African sleeping sickness and Chagas′ disease. Diaryl sulfides with a central anilino moiety, decorated with a flexible N-alkyl side chain bearing a terminal ammonium ion, are a known class of inhibitors. Using computer modelling, we revised the binding model for this class of TR inhibitors predicting simultaneous interactions of the ammonium ion-terminated N-alkyl chain with Glu18 as well as Glu465′/Glu466′ of the second subunit of the homodimer, whereas the hydrophobic substituent of the aniline ring occupies the “mepacrine binding site” near Trp21 and Met113. Systematic alteration of the carboxylate-binding fragments and the diaryl sulfide core of the inhibitor scaffold provided evidence for the proposed binding mode. In vitro studies showed IC₅₀ values in the low micromolar to submicromolar range against Trypanosoma brucei rhodesiense as well as the malaria parasite Plasmodium falciparum.