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

Abstract

3-Nitrotriazole-based compounds belonging to various chemical subclasses were found to be very effective against Chagas disease both in vitro and in vivo after a short administration schedule. In this study, five compounds with specific characteristics were selected to be administered for longer periods of time to mice infected with the virulent Trypanosoma cruzi Y strain to further evaluate their effectiveness as antichagasic agents and whether or not potential adverse effects occur. Benznidazole was included for comparison purposes. Complete parasitemia depletion, weight gain, 100% survival, and a lack of myocardial inflammation were observed with four of the compounds and benznidazole administered intraperitoneally at 15 or 20 mg/kg of body weight/day for 40 days. There was a significant reduction in the number of treatment days (number of doses) necessary to induce parasitemia suppression with all four compounds compared to that required with benznidazole. Partial cures were obtained with only one compound tested at 15 mg/kg/day and on the schedule mentioned above but not with benznidazole. Taken together, our data suggest that these compounds demonstrate potent trypanocidal activity comparable to or better than that of the reference drug, benznidazole, when they are administered at the same dose and on the same schedule.

Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy

“…A close analogue of the HAT clinical candidate SCYX-7158 (7), oxaborole SCYX-6759 (8), also exhibited strong in vivo activity against CD but was not curative in the chronic model [17]. Amongst many novel lead molecules evaluated in mice [18][19][20][21], the most promising was proteasome inhibitor GNF6702 (9), which delivered an 88% cure rate for treating chronic infection when dosed twice daily for 20 days [22]. Nevertheless, a five day schedule using higher doses of 9 did not achieve any cures in the acute model [23], and a new article by Rao et al [24] that compares 9 with a more recent analogue (for HAT) still provides no indication whether this pan-kinetoplastid drug candidate has progressed beyond preclinical toxicology.…”

Review on Experimental Treatment Strategies Against Trypanosoma cruzi

“…In infected mice, the analogues exhibited lower potency and higher toxic than BNZ. [ 68–76 ] [ 58 ] Fexinidazole Fexinidazole was more effective than BNZ, with cure rate greater than 70% in animals infected by different strains and treated during the acute or chronic phases. [ 46–48 ] Fexinidazole metabolites Fexinidazole sulfone and fexinidazole sulfoxide induced higher cure rates than fexinidazole.…”

“…Nitro-triazoles displayed in vitro anti- T. cruzi activity and induced the reduction of parasitemia in acute model of infection. 68–76 …”

“…Nitro-triazoles displayed in vitro anti-T. cruzi activity and induced the reduction of parasitemia in acute model of infection. [68][69][70][71][72][73][74][75][76] An important drug target for Chagas disease treatment is cruzipain (also named cruzain), an essential cysteine protease of T. cruzi responsible for the proteolytic activity in all stages of parasite life 77 . K777, a vinyl sulfone cruzipain inhibitor, exhibited anti-T. cruzi activity and induced the cure in experimental murine models (Figure 3).…”