A series of novel 2-nitro-1H-imidazole- and 3-nitro-1H-1,2,4-triazole-based aromatic and aliphatic amines were screened for anti-trypanosomal activity and mammalian cytotoxicity by the Drugs for Neglected Diseases initiative (DNDi). Out of 42 compounds tested, eighteen 3-nitro-1,2,4-triazoles and one 2-nitroimidazole displayed significant growth inhibitory properties against T. cruzi amastigotes (IC50 ranging from 40 nM to 1.97 μM), without concomitant toxicity towards the host cells (L6 cells), having selectivity indices (SI) 44 to 1320. Most (16) of these active compounds were up to 33.8-fold more potent than the reference drug benznidazole, tested in parallel. Five novel 3-nitro-1,2,4-triazoles were active against bloodstream form (BSF) T. b. rhodesiense trypomastigotes (IC50 at nM levels and SI 220 to 993). An NADH-dependent nitroreductase (TbNTR) plays a role in the anti-parasitic activity, since BSF T. b. brucei trypomastigotes with elevated TbNTR levels were hypersensitive to tested compounds. Therefore, a novel class of affordable 3-nitro-1,2,4-triazole-based compounds with antitrypanosomal activity has been identified.

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A series of novel 3-nitro-1H-1,2,4-triazole-(and in some cases 2-nitro-1H-imidazole)-based amides and sulfonamides were characterized for their in vitro anti-trypanosomal and antileishmanial activities as well as mammalian toxicity. Out of 36 compounds tested, 29 (mostly 3-nitro-1H-1,2,4-triazoles) displayed significant activity against T. cruzi intracellular amastigotes (IC50 ranging from 28 nM to 3.72 μM) without concomitant toxicity to L6 host cells (selectivity 66 to 2782). Twenty three of these active compounds were more potent (up to 58 fold) than the reference drug benznidazole, tested in parallel. In addition, 9 nitrotriazoles which were moderately active (0.5 μM ≤ IC50 < 6.0 μM) against T. b. rhodesiense trypomastigotes, were 5 to 31 fold more active against bloodstream-form T. b. brucei trypomastigotes engineered to overexpress NADH-dependent nitroreductase (TbNTR). Finally, 3 nitrotriazoles displayed a moderate activity against the axenic form of Leishmania donovani. Therefore, 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides are potent anti-trypanosomal agents.

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3-Nitro-1H-1,2,4-triazole-based amides with a linear, rigid core and 3-nitrotriazole-based fluconazole analogs were synthesized as dual functioning antitrypanosomal agents. Such compounds are excellent substrates for type I nitroreductase (NTR) located in the mitochondrion of trypanosomatids and, at the same time, act as inhibitors of the sterol 14α-demethylase (T. cruzi CYP51) enzyme. Because combination treatments against parasites are often superior to monotherapy, we believe that this emerging class of bifunctional compounds may introduce a new generation of antitrypanosomal drugs. In the present work, the synthesis and in vitro and in vivo evaluation of such compounds is discussed.