Alkylated Piperazines and Piperazine-Azole Hybrids as Antifungal Agents

J Med Chem. 2018 Jan 11;61(1):158-173. doi: 10.1021/acs.jmedchem.7b01138. Epub 2017 Dec 19.


The extensive use of fluconazole (FLC) and other azole drugs has caused the emergence and rise of azole-resistant fungi. The fungistatic nature of FLC in combination with toxicity concerns have resulted in an increased demand for new azole antifungal agents. Herein, we report the synthesis and antifungal activity of novel alkylated piperazines and alkylated piperazine-azole hybrids, their time-kill studies, their hemolytic activity against murine erythrocytes, as well as their cytotoxicity against mammalian cells. Many of these molecules exhibited broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against non-albicans Candida and Aspergillus strains. The most promising compounds were found to be less hemolytic than the FDA-approved antifungal agent voriconazole (VOR). Finally, we demonstrate that the synthetic alkylated piperazine-azole hybrids do not function by fungal membrane disruption, but instead by disruption of the ergosterol biosynthetic pathway via inhibition of the 14α-demethylase enzyme present in fungal cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-alpha Demethylase Inhibitors / chemistry
  • 14-alpha Demethylase Inhibitors / metabolism
  • 14-alpha Demethylase Inhibitors / pharmacology
  • 14-alpha Demethylase Inhibitors / toxicity
  • Alkylation
  • Animals
  • Antifungal Agents / chemistry*
  • Antifungal Agents / metabolism
  • Antifungal Agents / pharmacology*
  • Antifungal Agents / toxicity
  • Aspergillus / drug effects
  • Azoles / chemistry*
  • Candida albicans / drug effects
  • Cell Line
  • Hemolysis / drug effects
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Piperazines / chemistry*
  • Piperazines / metabolism
  • Piperazines / pharmacology*
  • Piperazines / toxicity
  • Protein Conformation
  • Sterol 14-Demethylase / chemistry
  • Sterol 14-Demethylase / metabolism


  • 14-alpha Demethylase Inhibitors
  • Antifungal Agents
  • Azoles
  • Piperazines
  • Sterol 14-Demethylase