Combating fluconazole-resistant fungi with novel β-azole-phenylacetone derivatives

Eur J Med Chem. 2019 Dec 1:183:111689. doi: 10.1016/j.ejmech.2019.111689. Epub 2019 Sep 13.

Abstract

A series of β-azole-phenylacetone derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible fungal infections and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against five susceptible strains and five fluconazole-resistant strains. Antifungal activity tests showed that most of the compounds exhibited excellent antifungal activities against five pathogenic strains with MIC values in the range of 0.03-1 μg/mL. Compounds with R1 = 3-F substituted and 15o and 15ae exhibited moderate antifungal activities against fluconazole-resistant strains 17# and CaR with MIC values in the range of 1-8 μg/mL. Compounds with R1 = H or 2-F (such as 15a, 15o, 15p) displayed moderate to good antifungal activity against fluconazole-resistant strains 632, 901 and 904 with MIC values in the range of 0.125-4 μg/mL. Notably, 15o and 15ae exhibited antifungal activity against five susceptible strains and five fluconazole-resistant strains. Preliminary mechanistic studies showed that the potent antifungal activity of compound 15ae stemmed from inhibition of C. albicans CYP51. Compounds 15o, 15z and 15ae were nearly nontoxic to mammalian A549 cells.

Keywords: Azole antifungals; CYP51; Fluconazole-resistance; Structure-activity relationship.

MeSH terms

  • A549 Cells
  • Acetone / analogs & derivatives*
  • Acetone / chemistry
  • Acetone / pharmacology
  • Antifungal Agents / chemical synthesis
  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology*
  • Azoles / chemistry
  • Azoles / pharmacology*
  • Candida albicans / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Fungal / drug effects*
  • Fluconazole / chemistry
  • Fluconazole / pharmacology*
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antifungal Agents
  • Azoles
  • Acetone
  • Fluconazole
  • 1-phenyl-2-propanone