Details

Autor(en) / Beteiligte

• Shrestha, Sanjib K.
• Garzan, Atefeh
• Garneau-Tsodikova, Sylvie

Titel

Novel alkylated azoles as potent antifungals

Ist Teil von

• European journal of medicinal chemistry, 2017-06, Vol.133, p.309-318

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2017

Quelle

ScienceDirect

Beschreibungen/Notizen

• Fluconazole (FLC) is the drug of choice when it comes to treat fungal infections such as invasive candidiasis in humans. However, the widespread use of FLC has resulted in the development of resistance to this drug in various fungal strains and, simultaneously has occasioned the need for new antifungal agents. Herein, we report the synthesis of 27 new FLC derivatives along with their antifungal activity against a panel of 13 clinically relevant fungal strains. We also explore their toxicity against mammalian cells, their hemolytic activity, as well as their mechanism of action. Overall, many of our FLC derivatives exhibited broad-spectrum antifungal activity and all compounds displayed an MIC value of <0.03 μg/mL against at least one of the fungal strains tested. We also found them to be less hemolytic and less cytotoxic to mammalian cells than the FDA approved antifungal agent amphotericin B. Finally, we demonstrated with our best derivative that the mechanism of action of our compounds is the inhibition of the sterol 14α-demethylase enzyme involved in ergosterol biosynthesis. [Display omitted] •Alkylated azole derivatives are more potent than their parent counterparts.•Alkylated azoles are less hemolytic and less toxic than non-alkylated azoles.•Alkylated azoles inhibit the ergosterol biosynthetic pathway.