Betraying the Parasite’s Redox System: Diaryl Sulfide‐Based Inhibitors of Trypanothione Reductase: Subversive Substrates and Antitrypanosomal Properties

Trypanosoma and Leishmania are the causative agents of African sleeping sickness (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi), and the different forms of leishmaniasis (for example, Leishmania donovani). All these tropical diseases cause many thousands of deaths annually, and African sleeping sickness and leishmaniasis are categorized as an emerging or uncontrolled (category 1) disease by the world health organization (WHO). The drugs currently in use show severe side effects, are often difficult to administrate, and are inefficient in the late stages of infection. In addition, the parasites show increasing drug resistance. This generates the urgent need for new antiparasitic agents. A promising approach in the fight against these diseases is to interfere with the redox metabolism of the parasites. In trypanosomatids, the nearly ubiquitous glutathione system is replaced by a trypanothione system. The key enzyme of the unique thiol metabolism is trypanothione reductase (TR, EC 1.8.1.12) which catalyzes the reduction of trypanothione disulfide (TS2, 1) to trypanothione (T(SH)2, 2) (Scheme 1). The NADPH dependent flavoprotein is the complement of human glutathione reductase (hGR, EC 1.8.1.7) and is essential for the parasites, rendering the enzyme an attractive drug target. An artful option to increase the efficiency of compounds interfering with redox enzymes such as TR is to incorporate structural motives into inhibitors, enabling them to convert the antioxidative disulfide reductase into a pro-oxidative enzyme. Redox-active compounds capable of such transformations have been termed turncoat inhibitors or subversive substrates. Distinguished by a functional group with a low one-electron reduction potential, such a subversive substrate X can be reduced by the flavoprotein to a radical anion X C, which can be reoxidized by molecular oxygen liberating superoxide anion radicals [Equations (1) and (2)] . This enzyme-catalyzed redox cycling process leads to the prodigality of NADPH and molecular oxygen, and the simultaneous release of toxic reactive oxygen species inside the parasites. Such compounds therefore act as catalysts for oxidative stress. The known sensitivity of parasitic protozoa towards reagents promoting free radical damage in cells renders this strategy a promising route to new, potent agents against the pathogens.