Wydział Chemii

Andreia Bento-Oliveira

Radosław Starosta

Rodrigo F. M. de Almeida

2024

Archives of Biochemistry and Biophysics

753

109919/1-109919/13

10.1016/j.abb.2024.109919

Naukowa

Angielski

Artykuł

Ketoconazole (Ke) is an important antifungal drug, and two of its diphenylphosphinemethyl derivatives (KeP: Ph₂PCH₂-Ke and KeOP: Ph₂P(O)CH₂-Ke) have shown improved antifungal activity, namely against a yeast strain lacking ergosterol, suggesting alternative modes of action for azole compounds. In this context, the interactions of these compounds with a model of the cell membrane were investigated, using POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) large unilamellar vesicles and taking advantage of the intrinsic fluorescence of Ke, KeP and KeOP. Steady-state fluorescence spectra and anisotropy, including partition and aggregation studies, as well as fluorescence lifetime measurements, were carried out. In addition, the ability of the compounds to increase membrane permeability was assessed through carboxyfluorescein leakage. The membrane/water mole fraction partition coefficients (K_p,x): (3.31 ± 0.36) x10⁵, (8.31 ± 1.60) x10⁵ and (4.66 ± 0.72) x10⁶, for Ke, KeP and KeOP, respectively, show that all three compounds have moderate to high affinity for the lipid bilayer. Moreover, KeP, and particularly KeOP interact more efficiently with POPC bilayers than Ke, which correlates well with their in vitro antifungal activity. Furthermore, although the three compounds disturb the lipid bilayer, KeOP is the quickest and most efficient one. Hence, the higher affinity and ability to permeabilize the membrane of KeOP when compared to that of KeP, despite the higher lipophilicity of the latter, points to an important role of Ph₂P(O)CH₂- oxygen. Overall, this work suggests that membrane interactions are important for the antifungal activity of these azoles and should be considered in the design of new therapeutic agents.

Ketoconazole, Drug-membrane interaction, Antifungal agents, Fluorescence spectroscopy, Diphenylphosphinomethyl derivatives, Phospholipid bilayer

CC-BY

http://dx.doi.org/10.1016/j.abb.2024.109919

http://www.elsevier.com