Novel 3-nitro-1H-1,2,4-triazole-based compounds as potential anti-Chagasic drugs: in vivo studies

Abstract

Background: Chagas disease is caused by the parasite Trypanosoma cruzi, is endemic in Latin America and leads to an estimated 14,000 deaths per year and around 100 million people at risk of infection. Drugs currently used in the treatment of Chagas are old, partially effective and have numerous side effects.

Methodology: We have previously reported that 3-nitro-1H-1,2,4-triazole-based compounds demonstrate significant and selective activity against T. cruzi amastigotes in infected L6 cells via activation of a type I nitroreductase, specific to trypanosomatids. In the present work we evaluated in vivo 13 of these compounds based on their high in vitro potency against T. cruzi (IC50 < 1 µM) and selectivity (SI: toxicity to L6 cells/toxicity against T. cruzi amastigotes > 200). Representative compounds of different chemical classes were included. A fast luminescence assay with transgenic parasites that express luciferase, and live imaging techniques were used. A total of 11 out of 13 compounds demonstrated significant antichagasic activity when administered intraperitoneally for 5-10 days at relatively small doses. The best in vivo activity was demonstrated by amides and sulfonamide derivatives. ADMET studies were performed for specific compounds.

Conclusion: At least three compounds were identified as effective, non-toxic antichagasic agents suitable for further development.

Figure 1. In vivo evaluation of compounds in Table 1

Parasite index was determined after 5- and 10-day treatment at the indicated doses. For compounds 1 and 5, parasite index was determined only after 10-day treatment, whereas for compound 6 after 5-day treatment only. Errors indicate SD. *p ≤ 0.05; **p ≤ 0.01.

Figure 2. Images of untreated and treated mice with the indicated compounds

Groups of five mice were infected with Trypanosoma cruzi trypomastigotes expressing luciferase and imaged before and after 5- and 10-day treatment.

Figure 3. Images of untreated and treated mice with the indicated compounds

Groups of five mice were infected with Trypanosoma cruzi trypomastigotes expressing luciferase and imaged before and after 5- and 10-day treatment.

Figure 4. Mutagenicity study (Ames test) for compound 4 in TA98 strains without/with S9

PC was 625/1200 ng/ml 4-nitroquinoline-N-oxide/2-nitrofluorene (−S9) and 2-aminoanthracene (+S9). PC: Positive control.

Figure 5. Mutagenicity study (Ames test) for compound 4 in mixed TA7001–7006/strains without/with S9

PC: −S9-Mix: 625/1200 ng/ml 4-nitroquinoline-N-oxide/2-nitrofluorene; +S9-Mix:10 µg/ml 2-aminoanthracene. *p ≤ 0.05; **p ≤ 0.01.