Design, synthesis and evaluation of novel 5-phenylthiophene derivatives as potent fungicidal of Candida albicans and antifungal reagents of fluconazole-resistant fungi

Eur J Med Chem. 2021 Dec 5:225:113740. doi: 10.1016/j.ejmech.2021.113740. Epub 2021 Aug 9.

Abstract

A series of 5-phenylthiophene derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against seven susceptible strains and six fluconazole-resistant strains. It is especially encouraging that compounds 17b and 17f displayed significant antifungal activities against all tested strains. Furthermore, the potent compounds 17b and 17f could prevent the formation of fungi biofilms and 17f displayed satisfactory fungicidal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 17f stemmed from inhibition of C. albicans CYP51. In addition, Compounds 17b and 17f were almost nontoxic to mammalian A549, MCF-7, and THLE-2 cells. These results strongly suggested that compounds 17b and 17f are promising as novel antifungal drugs.

Keywords: Azole antifungals; CYP51; Fluconazole-resistance; Fungicidal agents.

MeSH terms

  • Antifungal Agents / chemical synthesis
  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology*
  • Candida albicans / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Resistance, Fungal / drug effects
  • Fluconazole / pharmacology
  • Fungicides, Industrial / chemical synthesis
  • Fungicides, Industrial / chemistry
  • Fungicides, Industrial / pharmacology*
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*

Substances

  • Antifungal Agents
  • Fungicides, Industrial
  • Thiophenes
  • Fluconazole