Nivel 1,2-Dithiins: Synthesis, Molecular Modeling Studies, and Antifungal Activity

Article abstract of DOI:10.1021/jm00014a016

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 β-mercaptopropionitrile as the thiophile, relying on a β-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.