Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives

Abstract

The study presented here aimed at identifying a new class of compounds acting against Leishmania parasites, the causative agent of Leishmaniasis. For this purpose, the thioether derivatives of our in-house library have been evaluated in whole-cell screening assays in order to determine their in vitro activity against Leishmania protozoan. Among them, promising results have been achieved with compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine) (IC₅₀=29.43 µM), which is able to impair the mechanism of the parasite defence against the reactive oxygen species by inhibiting the trypanothione reductase (TR) with high efficiency (K_i 0.25 ± 0.18 µM). The X-ray structure of L. infantum TR in complex with RDS 777 disclosed the mechanism of action of this compound that binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding and avoiding its reduction.

Keywords:

• Diaryl sulfide derivatives
• Leishmania infantum
• trypanothione reductase
• trypanothione reductase inhibition
• X-ray crystal structure

Acknowledgements

We gratefully acknowledge the Helmholtz-Zentrum Berlin – Electron storage ring BESSY II for providing synchrotron radiation at beamline BL14–1. from the European Community's Seventh Framework Program (FP7/2007–2013) under BioStruct-X (grant agreement no. 283570) and Bag Project 1223, CNCCS CNR (National Collection of Chemical Compounds and Screening Center 2015) to AI.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

CNCCS CNR (National Collection of Chemical Compounds and Screening Center 2015) [B56G15001140005].