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Design and synthesis of new 1,2,3-triazoles derived from eugenol and analogues with in vitro and in vivo activity against Trypanosoma cruzi. | LitMetric

AI Article Synopsis

  • Chagas disease (CD) affects approximately 8 million people across 21 countries and primarily relies on two drugs, which have significant limitations such as low cure rates, high toxicity, and rising resistance from the parasite T. cruzi.
  • Recent research identified a new compound (1,2,3-triazole derivative 35) that showed promising in vitro and in vivo activity against T. cruzi, leading to the development of new derivatives that displayed even more potent antiprotozoal properties.
  • Among these, compounds 26 and 27 exhibited significantly lower toxicity to healthy cells compared to standard treatments and displayed effective trypanocidal activity, suggesting a potential new avenue for treating Chagas disease despite their mechanism of action not being

Article Abstract

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 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 19.7 μM) and 27 (IC 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 20.74 μM) and 27 (IC 8.41 μM), mainly 27 which showed activity once again higher than that observed for benznidazole (IC 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.

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http://dx.doi.org/10.1016/j.ejmech.2023.115622DOI Listing

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