Novel alkylated azoles as potent antifungals

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

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)309-318
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume133
DOIs
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Masson SAS

Keywords

  • Cytotoxicity
  • Ergosterol
  • Fluconazole
  • Hemolysis
  • Time-kill curves

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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