Antifungal Phenothiazines: Optimization, Characterization of Mechanism, and Modulation of Neuroreceptor Activity

ACS Infect Dis. 2018 Apr 13;4(4):499-507. doi: 10.1021/acsinfecdis.7b00157. Epub 2017 Nov 2.


New classes of antifungal drugs are an urgent unmet clinical need. One approach to the challenge of developing new antifungal drugs is to optimize the antifungal properties of currently used drugs with favorable pharmacologic properties, so-called drug or scaffold repurposing. New therapies for cryptococcal meningitis are particularly important given its worldwide burden of disease and limited therapeutic options. We report the first systematic structure-activity study of the anticryptococcal properties of the phenothiazines. We also show that the antifungal activity of the phenothiazine scaffold correlates well with its calmodulin antagonism properties and, thereby, provides the first insights into the mechanism of its antifungal properties. Guided by this mechanism, we have generated improved trifluoperazine derivatives with increased anticryptococcal activity and, importantly, reduced affinity for receptors that modulate undesired neurological effects. Taken together, these data suggest that phenothiazines represent a potentially useful scaffold for further optimization in the search for new antifungal drugs.

Keywords: Candida; Cryptococcus neoformans; antifungal; phenothiazine; repurposing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology*
  • Antipsychotic Agents / chemical synthesis
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology*
  • Candida albicans / drug effects
  • Cryptococcus neoformans / drug effects*
  • Drug Repositioning / methods*
  • Inhibitory Concentration 50
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Phenothiazines / chemical synthesis
  • Phenothiazines / chemistry
  • Phenothiazines / pharmacology*
  • Sensory Receptor Cells / metabolism*
  • Structure-Activity Relationship


  • Antifungal Agents
  • Antipsychotic Agents
  • Phenothiazines