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Membrane insertion properties of ketoconazole derivatives: Elucidating the path to fight drug resistant fungal infections
Autorzy
Rok wydania
2025
Czasopismo
Numer woluminu
425
Strony
127195/1-127195/14
DOI
10.1016/j.molliq.2025.127195
Kolekcja
Język
Angielski
Typ publikacji
Artykuł
The addition of a diphenylphosphine or diphenylphosphine oxide motif to the antifungal ketoconazole (Ke) resulted in the derivative KeP (Ph2PCH2-Ke) or KeOP (Ph2P(O)CH2-Ke) characterized by improved antifungal activity which could be related with their increased membrane permeabilizing ability. To tackle how these motifs modulate the compounds-membrane interaction, ultimately leading to improved antifungal activity, we studied 4MP (Ph2PCH2-pip-C6H4-4-OMe) and its oxide (4MOP) – two structurally simplified analogs of KeP and KeOP in solution and their interaction with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) large unilamellar vesicles. The mole fraction membrane/water partition coefficient determined through their intrinsic fluorescence was (4.29 ± 0.17) × 104 and (5.21 ± 0.82) × 105, showing that the interaction of these hydrophobic analogs with the membrane is less favorable than for KeP and KeOP. Fluorescence quenching by acrylamide, revealed that 4MP and 4MOP lie near the surface of the lipid bilayer, in contrast with Ke, KeP, and KeOP. Furthermore, a permeability assay with carboxyfluorescein showed that neither 4MP nor 4MOP change markedly the permeability of POPC membranes and that KeOP induced the fastest and most extensive membrane leakage. All the results show that the simultaneous presence of Ke and the phosphine moiety affords a deep and effective membrane interaction, but the oxygen involved in a P=O bond within the phosphine oxide is crucial to observe significantly increased membrane affinity and permeabilization. The use of fluorescent probes Laurdan and DPH further revealed that KeOP enhances water penetration into the hydrophobic core of the POPC bilayer, explaining at the molecular level the highest efficiency of this compound to permeabilize the membrane and antifungal activity, particularly against ketoconazole-resistant strains.
Słowa kluczowe
Drug-membrane interaction, Antifungal agents, Fluorescence spectroscopy, Diphenylphosphinomethyl derivatives, Phospholipid bilayer
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Pełny tekst licencji: https://creativecommons.org/licenses/by/3.0/pl/legalcode
Adres publiczny
http://dx.doi.org/10.1016/j.molliq.2025.127195
Strona internetowa wydawcy
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