NOVEL 1,2-DITHIINS - SYNTHESIS, MOLECULAR MODELING STUDIES, AND ANTIFUNGAL ACTIVITY

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 ki logram 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. Opti mal geometries of dithiins 1d, 18i, and 45 and model dithiin 61 were d etermined by molecular mechanics and Hartree-Fock molecular orbital ca lculations. Two possible mechanisms of action are presented for the 1, 2-dithiin class of compounds to explain their observed antifungal acti vities against Candida albicans, Cryptococcus neoformans, and Aspergil lus fumigatus.