1. Academic Validation
  2. New miconazole-based azoles derived from eugenol show activity against Candida spp. and Cryptococcus gattii by inhibiting the fungal ergosterol biosynthesis

New miconazole-based azoles derived from eugenol show activity against Candida spp. and Cryptococcus gattii by inhibiting the fungal ergosterol biosynthesis

  • Eur J Med Chem. 2023 Aug 5:256:115436. doi: 10.1016/j.ejmech.2023.115436.
Vinícius Augusto Campos Péret 1 Rúbia Castro Fernandes Melo Reis 1 Saulo Fehelberg Pinto Braga 1 Monique Dias Benedetti 2 Ivo Santana Caldas 2 Diogo Teixeira Carvalho 3 Luiz Felipe de Andrade Santana 4 Susana Johann 4 Thiago Belarmino de Souza 5
Affiliations

Affiliations

  • 1 School of Pharmacy - Federal University of Ouro Preto, 35400-000, Ouro Preto, MG, Brazil.
  • 2 Institute of Biomedical Sciences - Federal University of Alfenas, Alfenas, Brazil.
  • 3 Pharmaceutical Sciences Faculty - Federal University of Alfenas, 37130-001, Alfenas, MG, Brazil.
  • 4 Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil.
  • 5 School of Pharmacy - Federal University of Ouro Preto, 35400-000, Ouro Preto, MG, Brazil. Electronic address: thiago.souza@ufop.edu.br.
Abstract

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.

Keywords

CYP-51; Candida auris; Candida spp.; Ergosterol; Eugenol; New azoles.

Figures
Products