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 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.
Bierer
D E
DE
Shaman Pharmaceuticals, Inc., South San Francisco, California 94080-4812, USA.
Dener
J M
JM
Dubenko
L G
LG
Gerber
R E
RE
Litvak
J
J
Peterli
S
S
Peterli-Roth
P
P
Truong
T V
TV
Mao
G
G
Bauer
B E
BE
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
D000935:Antifungal Agents; D006571:Heterocyclic Compounds