Novel 1,2-dithiins: synthesis, molecular modeling studies, and antifungal activity

J Med Chem. 1995 Jul 7;38(14):2628-48. doi: 10.1021/jm00014a016.

Abstract

The first structure-activity study involving the 1,2-dithiin class of compounds (1,2-dithiacyclohexadienes) is herein reported. A series of 3,6-disubstituted 1,2-dithiins was synthesized from dithiins 1d and 1e and evaluated as antifungal agents. A new and versatile synthesis of dithiins 1d and 1e is reported which is amenable to scale-up at the kilogram level. The novelty of the process derives from the use of beta-mercaptopropionitrile as the thiophile, relying on a beta-elimination strategy and subsequent oxidation to create the 1,2-dithiin ring. Optimal geometries of dithiins 1d, 18i, and 45 and model dithiin 61 were determined by molecular mechanics and Hartree-Fock molecular orbital calculations. Two possible mechanisms of action are presented for the 1,2-dithiin class of compounds to explain their observed antifungal activities against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus.

MeSH terms

  • Antifungal Agents / chemical synthesis*
  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology
  • Aspergillus fumigatus / drug effects
  • Candida albicans / drug effects
  • Cryptococcus neoformans / drug effects
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology
  • Magnetic Resonance Spectroscopy
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Structure-Activity Relationship

Substances

  • Antifungal Agents
  • Heterocyclic Compounds