Search

Chagas disease (CD) is a neglected tropical disease endemic in 21 countries and affects about 8 million people around the world. The pharmacotherapy for this disease is limited to two drugs (Benznidazole and Nifurtimox) and both are associated with important limitations, as low cure rate in the chronic phase of the disease, high toxicity and increasing resistance by Trypanosoma cruzi. Recently, we reported a bioactive 1,2,3-triazole (compound 35) active in vitro (IC 50 42.8 μM) and in vivo (100 mg/kg) against T. cruzi Y strains and preliminary in silico studies suggested the cysteine protease cruzain as a possible target. Considering these initial findings, we describe here the design and synthesis of new 1,2,3-triazoles derivatives of our hit compound (35). The triazoles were initially evaluated against healthy cells derived from neonatal rat cardiomyoblasts (H9c2 cells) to determine their cytotoxicity and against epimastigotes forms of T. cruzi Y strain. The most active triazoles were compounds 26 (IC 50 19.7 μM) and 27 (IC 50 7.3 μM), while benznidazole was active at 21.6 μM. Derivative 27 showed an interesting selectivity index considering healthy H9c2 cells (>77). Promising activities against trypomastigotes forms of the parasite were also observed for triazoles 26 (IC 50 20.74 μM) and 27 (IC 50 8.41 μM), mainly 27 which showed activity once again higher than that observed for benznidazole (IC 50 12.72 μM). While docking results suggested cruzain as a potential target for these compounds, no significant enzyme inhibition was observed in vitro, indicating that their trypanocidal activity is related to another mode of action. Considering the promising in vitro results of triazoles 26 and 27, the in vivo toxicity was initially verified based on the evaluation of behavioral and physiological parameters, mortality, effect in body weight gain, and through the measurement of AST/ALT enzymes, which are markers of liver toxicity. All these evaluations pointed to a good tolerability of the animals, especially considering triazole 27. A reduction in parasitemia was observed among animals treated with triazole 27, but not among those treated with derivative 26. Regarding the dosage, derivative 27 (100 mg/kg) was the most active sample against T. cruzi infection, showing a 99.4% reduction in parasitemia peak. Triazole 27 at a dosage of 100 mg/kg influenced the humoral immune response and reduced myocarditis in the animals, bringing antibody levels closer to those observed among healthy mice. Altogether, our results indicate compound 27 as a new lead for the development of drug candidates to treat Chagas disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Ayahuasca is a psychoactive and psychedelic decoct composed mainly of Banisteriopsis caapi and Psychotria viridis plant species. The beverage is rich in alkaloids and it is ritualistically used by several indigenous communities of South America as a natural medicine. There are also reports in the literature indicating the prophylaxis potential of Ayahuasca alkaloids against internal parasites. In the present study, Ayahuasca exhibited moderate in vitro activity against Trypanosoma cruzi trypomastigotes (IC 50 95.78 μg/mL) compared to the reference drug benznidazole (IC 50 2.03 μg/mL). The β-carboline alkaloid harmine (HRE), isolated from B. caapi, was considered active against the trypomastigotes forms (IC 50 6.37), and the tryptamine N, N-dimethyltryptamine (DMT), isolated from P. viridis was also moderately active with IC 50 of 21.02 μg/mL. Regarding the in vivo evaluations, no collateral effects were observed. The HRE alone demonstrated the highest trypanocidal activity in a dose-responsive manner (10 and 100 mg/kg). The Ayahuasca and the association between HRE and DMT worsened the parasitaemia, suggesting a modulation of the immunological response during the T. cruzi infection, especially by increasing total Immunoglobulin (IgG) and IgG1 antibody levels. The in silico molecular docking revealed HRE binding with low energy at two sites of the Trypanothione reductase enzyme (TR), which are absent in humans, and thus considered a promissory target for drug discovery. In conclusion, Ayahuasca compounds seem to not be toxic at the concentrations of the in vivo evaluations and can promote trypanocidal effect in multi targets, including control of parasitaemia, immunological modulation and TR enzymatic inhibition, which might benefit the treatments of patients with Chagas' disease. Moreover, the present study also provides scientific information to support the prophylactic potential of Ayahuasca against internal parasites., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

A series of 11 new N,S-acetal juglone derivatives were synthesized and evaluated against T. cruzi epimastigote forms. These compounds were obtained in good to moderate yields using a microwave irradiation protocol. Among all compounds, two N,S-acetal analogs, showed significant trypanocidal activity. Notably, one compound 11g exhibited selectivity index 10-fold higher than the reference drug benznidazole for epimastigote. The compound 11h was more effective for amastigote forms. Both prototypes exhibited S.I. higher than the benznidazole description. Thus, both compounds proving to be useful candidate molecules to further studies in infected animals.