Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation

Nitrotriazole-Based Compounds as Antichagasic Agents in a Long-Treatment In Vivo Assay

“…at a lower dose than compounds 1 and 2, namely, 15 mg/kg/day for 40 days. The high antichagasic potencies of these compounds may be attributed to their bifunctional character, since they are substrates of type I NTR and might act as inhibitors of the TcCYP51 enzyme (13). Compound 4 was included in the study because it had an efficacy profile in vitro similar to the profiles of compounds 3 and 5 (Table 1), despite the fact that it was not previously evaluated in the fast in vivo luminescence assay.…”

“…Compound 2, a 3-nitrotriazole-based amide, has been proven to be a substrate for type I NTR and a weak CYP51 reversible inhibitor due to its more rigid backbone core (12). Finally, compounds 3 to 5 are 3-nitrotriazole based aryloxyphenylamides activated by type I NTR and strong binders of T. cruzi CYP51 (TcCYP51), as has been demonstrated by docking studies (13).…”

“…We have demonstrated that various chemical classes of 3-nitro-1H-1,2,4-triazolebased compounds exhibit excellent antichagasic activity both in vitro and in vivo (7)(8)(9)(10)(11)(12)(13)(14)(15) and that this activity is in part due to their reductive activation by a type I nitroreductase (NTR) (7,8,(10)(11)(12)(13)(14)(15). Type I NTR is an oxygen-insensitive nitroreductase present in the mitochondrion of trypanosomatids and absent from most other eukaryotes (16)(17)(18)(19).…”

“…Moreover, 3-nitrotriazole-based compounds seem to be more potent and less toxic than their 2-nitroimidazole-based counterparts (7,8,10,20). Since azoles play a significant role in the inhibition of CYP51 (sterol 14␣-demethylase, an enzyme crucial for the formation of viable membranes and the regulation of metabolic processes) not only in fungi but also in trypanosomatids (21)(22)(23)(24), we have also developed subclasses of 3-nitrotriazole-based compounds that act as bifunctional antichagasic agents: they are substrates for type I NTR, in addition to being reversible inhibitors of T. cruzi CYP51 (12,13). The idea of making bifunctional compounds was based on the observation that combination therapy with multiple targets offers advantages compared to monotherapy (25,26).…”

“…The idea of making bifunctional compounds was based on the observation that combination therapy with multiple targets offers advantages compared to monotherapy (25,26). Indeed, such bifunctional compounds demonstrate remarkable antichagasic activity both in vitro and in a murine model of acute infection (12,13).…”