Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects

Abstract

There is an urgent need for new, safer, and effective treatments for the diseases caused by the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. In the search for more effective drugs to treat these 'neglected diseases' researchers have chosen to reassess the therapeutic value of nitroaromatic compounds. Previously avoided in drug discovery programs owing to potential toxicity issues, a nitro drug is now being used successfully as part of a combination therapy for human African trypanosomiasis. We describe here the rehabilitation of nitro drugs for the treatment of trypanosomatid diseases and discuss the future prospects for this compound class.

Keywords: bioactivation; nitroaromatics; nitroreductase; pro-drugs; trypanosomatids.

Figure 1

Selected anti-trypanosomatid nitroaromatics and their metabolites. Nitroaromatic compounds used to treat, or are in development for, trypanosomatid diseases. For fexinidazole, both the parent compound and the two metabolites resulting from in vivo oxidation are shown.

Figure 2

Mechanism of nitroreductase (NTR)-mediated bioactivation of nitroaromatic compounds. (A) Nifurtimox undergoes two sequential NTR-catalyzed reductions, followed by ring opening to give a toxic unsaturated open-chain nitrile. Tb, Trypanosoma brucei; Tc, Trypanosoma cruzi. (B) The nitro group of benznidazole is reduced to the hydroxylamine by NTR. Subsequently, a series of non-enzymatic transformations leads to a dihydro-dihydroxy product, which can release glyoxal. (C) Unusually, MtbDdn [deazaflavin (F₄₂₀)-dependent nitroreductase (Ddn) of Mycobacterium tuberculosis (Mtb)] does not reduce the nitro group of (S)-PA-824. Instead, the first step of the bioactivation involves reduction of the C2–C3 bond of the bicyclic imidazooxazine ring system. The unstable product of this reduction is protonated and then undergoes a des-nitrification reaction to give des-nitro-PA-824, with the concomitant production of nitrous acid. Some structures have been abbreviated for clarity. Compounds in square brackets are not experimentally detected. Adapted from .

Figure I

Alternative nitro group representations and examples of nitroaromatics.

Figure I

One- and two-electron reduction of nitroaromatics.