Synthesis and antifungal evaluation of pentyloxyl-diphenylisoxazoloyl pneumocandins and echinocandins

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3253-6. doi: 10.1016/j.bmcl.2013.03.115. Epub 2013 Apr 10.

Abstract

Echinocandins and pneumocandins are classes of lipocyclohexapeptides that are broad spectrum antifungal agents. They inhibit fungal specific 1,3-β-glucan synthase activity which is an essential component of the fungal cell wall. Chemical modifications of these two leads have produced three clinical agents namely caspofungin, micafungin and anidulafungin. The presence of hydroxy-glutamine versus threonine and unsaturated linear fatty acid versus branched chain saturated fatty acid differentiate the two classes of compounds with profound differences in their hemolytic properties. In the current study, we have replaced the side chain of the cyclohexapeptides with a common aromatic heterocyclic acyl side chain and compared the biological activities of the cores head-to-head and for the first time demonstrated the role played by the acyl chain and the hydroxy-glutamine for the antifungal potency.

MeSH terms

  • Animals
  • Antifungal Agents / chemical synthesis*
  • Antifungal Agents / pharmacology
  • Antifungal Agents / therapeutic use
  • Candida / drug effects
  • Candida / enzymology
  • Candidiasis / drug therapy
  • Caspofungin
  • Cell Wall / drug effects
  • Echinocandins / chemistry*
  • Echinocandins / pharmacology
  • Echinocandins / therapeutic use
  • Glucosyltransferases / antagonists & inhibitors
  • Glucosyltransferases / metabolism
  • Glutamine / chemistry
  • Isoxazoles / chemistry*
  • Lipopeptides
  • Mice
  • Microbial Sensitivity Tests
  • Protein Binding
  • Structure-Activity Relationship
  • Threonine / chemistry

Substances

  • Antifungal Agents
  • Echinocandins
  • Isoxazoles
  • Lipopeptides
  • Glutamine
  • Threonine
  • Glucosyltransferases
  • 1,3-beta-glucan synthase
  • Caspofungin