Antifungal Azole Derivatives Featuring Naphthalene Prove Potent and Competitive Cholinesterase Inhibitors with Potential CNS Penetration According to the in Vitro and in Silico Studies

Chem Biodivers. 2022 Jul;19(7):e202200027. doi: 10.1002/cbdv.202200027. Epub 2022 Jun 23.


Cholinesterase inhibition is of great importance in the fight against neurodegenerative disorders such as Alzheimer's disease. Azole antifungals have come under the spotlight with recent discoveries that underline the efficacy and potential of miconazole and its derivatives against cholinesterase enzymes. In this study, we evaluated a library of azoles against acetylcholinesterase and butyrylcholinesterase using in vitro and in silico methods to identify potent inhibitors. Low micromolar IC50 values were obtained for imidazole derivatives, which were further tested and found potent competitive cholinesterase inhibitors via enzyme kinetics study. The active derivatives showed negligible toxicity in in vitro cytotoxicity tests. Molecular modeling studies predicted that these derivatives were druglike, could penetrate blood-brain barrier, and tightly bind to cholinesterase active site making key interactions via the imidazole moiety at protonated state. Thus, current study identifies potent and competitive cholinesterase inhibitor azoles with minor toxicity and potential to pass into the central nervous system.

Keywords: acetylcholinesterase; butyrylcholinesterase; enzyme kinetics; imidazole; molecular docking.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease*
  • Antifungal Agents / pharmacology
  • Azoles / pharmacology
  • Butyrylcholinesterase / metabolism
  • Central Nervous System
  • Cholinesterase Inhibitors* / chemistry
  • Humans
  • Imidazoles
  • Molecular Docking Simulation
  • Naphthalenes
  • Structure-Activity Relationship


  • Antifungal Agents
  • Azoles
  • Cholinesterase Inhibitors
  • Imidazoles
  • Naphthalenes
  • Acetylcholinesterase
  • Butyrylcholinesterase