title: Novel alkylated azoles as potent antifungals.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536-0596, USA.
authors.forename: Sanjib K
authors.initials: SK
authors.lastname: Shrestha
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536-0596, USA.
authors.forename: Atefeh
authors.initials: A
authors.lastname: Garzan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536-0596, USA. Electronic address: sylviegtsodikova@uky.edu.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
mesh_terms: D000478:Alkylation; D000818:Animals; D000935:Antifungal Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001393:Azoles / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy; D002460:Cell Line; D004875:Ergosterol / Q000378:metabolism; D005658:Fungi / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D009181:Mycoses / Q000188:drug therapy*
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D004875:Ergosterol
keywords: Cytotoxicity; Ergosterol; Fluconazole; Hemolysis; Time-kill curves