Optimization of Potent and Specific Trypanothione Reductase Inhibitors: A Structure-Based Drug Discovery Approach

ACS Infect Dis. 2022 Aug 12;8(8):1687-1699. doi: 10.1021/acsinfecdis.2c00325. Epub 2022 Jul 26.


Leishmania spp. are responsible for up to 1 million new cases each year. The current therapeutic arsenal against Leishmania is largely inadequate, and there is an urgent need for better drugs. Trypanothione reductase (TR) represents a druggable target since it is essential for the parasite and not shared by the human host. Here, we report the optimization of a novel class of potent and selective LiTR inhibitors realized through a concerted effort involving X-ray crystallography, synthesis, structure-activity relationship (SAR) investigation, molecular modeling, and in vitro phenotypic assays. 5-Nitrothiophene-2-carboxamides 3, 6e, and 8 were among the most potent and selective TR inhibitors identified in this study. 6e and 8 displayed leishmanicidal activity in the low micromolar range coupled to SI > 50. Our studies could pave the way for the use of TR inhibitors not only against leishmaniasis but also against other trypanosomatidae due to the structural similarity of TR enzymes.

Keywords: Leishmania; sulfonamides; trypanothione; trypanothione reductase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Discovery
  • Humans
  • Leishmania*
  • Leishmaniasis* / drug therapy
  • NADH, NADPH Oxidoreductases


  • NADH, NADPH Oxidoreductases
  • trypanothione reductase