History of the development of antifungal azoles: A review on structures, SAR, and mechanism of action

Bioorg Chem. 2020 Nov:104:104240. doi: 10.1016/j.bioorg.2020.104240. Epub 2020 Aug 28.


With the increasing risk of invasive and life threating fungal infections, there is now a great concern regarding the lower discovery rate of antifungal drugs in comparison to antimicrobial agents. Drugs conventionally used in clinics are not adequate enough to combat the increasing fungal infections, especially fungal forms resistant to fluconazole. Among the limited antifungal agents in clinics, azoles have the largest number of drug candidates in clinical trials and are partly marketed due to the particular focus of pharmaceutical companies and medicinal scientific centers. With the rise in the number of papers on azole antifungal design and discovery, a more in-depth understanding the most recent and authentic information about this class of drugs might be beneficial. To this end, we for the first time summarized the state-of-the-art information about azole drugs, with a specific focus on those in the pipelines of pharmaceutical companies, into four generations with regard to their structural similarity. More importantly, this review highlights information on the structure activity relationship (SAR), target description, hybrid antifungal agents as possible future generation, and other useful issues to streamline research towards designing new efficient azole antifungal structures in future.

Keywords: Azole; Drug development; Invasive fungal infection; Lanosterol 14α-demethylase; Molecular hybrids; Structure activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology*
  • Azoles / chemistry
  • Azoles / pharmacology*
  • Dose-Response Relationship, Drug
  • Fungi / drug effects*
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Structure-Activity Relationship


  • Antifungal Agents
  • Azoles