New miconazole-based azoles derived from eugenol show activity against Candida spp. and Cryptococcus gattii by inhibiting the fungal ergosterol biosynthesis.
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2023
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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/spectro-
metric 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.
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New azoles, Candida auris
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PÉRET, V. A. C. et al. New miconazole-based azoles derived from eugenol show activity against Candida spp. and Cryptococcus gattii by inhibiting the fungal ergosterol biosynthesis. European Journal of Medicinal Chemistry, v. 256, artigo 115436, ago. 2023. Disponível em: <https://www.sciencedirect.com/science/article/pii/S0223523423004026>. Acesso em: 01 ago. 2023.