title: Novel 1,2-dithiins: synthesis, molecular modeling studies, and antifungal activity.
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.
authors.affiliation: Shaman Pharmaceuticals, Inc., South San Francisco, California 94080-4812, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Bierer
authors.forename: J M
authors.initials: JM
authors.lastname: Dener
authors.forename: L G
authors.initials: LG
authors.lastname: Dubenko
authors.forename: R E
authors.initials: RE
authors.lastname: Gerber
authors.forename: J
authors.initials: J
authors.lastname: Litvak
authors.forename: S
authors.initials: S
authors.lastname: Peterli
authors.forename: P
authors.initials: P
authors.lastname: Peterli-Roth
authors.forename: T V
authors.initials: TV
authors.lastname: Truong
authors.forename: G
authors.initials: G
authors.lastname: Mao
authors.forename: B E
authors.initials: BE
authors.lastname: Bauer
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D006571:Heterocyclic Compounds