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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.)

This work describes the design, synthesis and antifungal activity of new imidazoles and 1,2,4-triazoles derived from eugenol and dihydroeugenol. These new compounds were fully characterized by spectroscopy/spectrometric analyses and the imidazoles 9, 10, 13 e 14 showed relevant antifungal activity against Candida sp. and Cryptococcus gattii in the range of 4.6-75.3 μM. Although no compound has shown a broad spectrum of antifungal activity against all evaluated strains, some azoles were more active than either reference drugs employed against specific strains. Eugenol-imidazole 13 was the most promising azole (MIC: 4.6 μM) against Candida albicans being 32 times more potent than miconazole (MIC: 150.2 μM) with no relevant cytotoxicity (selectivity index >28). Notably, dihydroeugenol-imidazole 14 was twice as potent (MIC: 36.4 μM) as miconazole (MIC: 74.9 μM) and more than 5 times more active than fluconazole (MIC: 209.0 μM) against alarming multi-resistant Candida auris. Furthermore, in vitro assays showed that most active compounds 10 and 13 altered the fungal ergosterol biosynthesis, reducing its content as fluconazole does, suggesting the enzyme lanosterol 14α-demethylase (CYP51) as a possible target for these new compounds. Docking studies with CYP51 revealed an interaction between the imidazole ring of the active substances with the heme group, as well as insertion of the chlorinated ring into a hydrophobic cavity at the binding site, consistent with the behavior observed with control drugs miconazole and fluconazole. The increase of azoles-resistant isolates of Candida species and the impact that C. auris has had on hospitals around the world reinforces the importance of discovery of azoles 9, 10, 13 e 14 as new bioactive compounds for further chemical optimization to afford new clinically antifungal agents., 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.)