Development of Thiazolidinones as Fungal Carbonic Anhydrase Inhibitors

Int J Mol Sci. 2020 Apr 22;21(8):2960. doi: 10.3390/ijms21082960.

Abstract

In our efforts to find new and selective thiazolidinone-based anti-Candida agents, we synthesized and tested 26 thiazolidinones against several Candida spp. and Gram-positive and Gram-negative bacteria. The compounds showed selective antifungal activity with potency similar to fluconazole and clotrimazole, while lacking strong antibacterial activity. Molecular docking and molecular dynamics studies were performed on Candida CYP51a1 and carbonic anhydrase (CA) enzymes to further suggest putative targets that could mediate the antifungal effects of these compounds. Finally, the compounds were tested in enzyme inhibition assays to assess their putative mechanism of action and showed promising KI values in the 0.1-10 µM range against the Candida glabrata β-CA enzyme CgNce103.

Keywords: 4-thiazolidinones; CYP51a1; CgNce103; antifungal activity; carbonic anhydrases; lanosterol 14α-demethylase; molecular modelling studies.

MeSH terms

  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology*
  • Binding Sites
  • Candida / drug effects
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Catalytic Domain
  • Drug Development*
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Antifungal Agents
  • Carbonic Anhydrase Inhibitors