Inhibition of sterol 14 alpha-demethylation of Candida albicans with NND-502, a novel optically active imidazole antimycotic agent.
To investigate the mode of action of the newly synthesized optically active imidazole compound, NND-502, (-)-(E)-[4-(2, 4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonit rile, its effect on ergosterol biosynthesis in cell-free extracts of Candida albicans was examined and compared with that of the (S)-enantiomer of NND-502 in addition to lanoconazole and bifonazole, both of which are clinically used for the treatment of dermatomycoses. NND-502 was found to interfere with ergosterol biosynthesis by inhibition of sterol 14alpha-demethylase, while no interference due to the (S)-enantiomer of NND-502 was found, indicating that the stereochemical orientation of the 2, 4-dichlorophenyl group plays an important role in the interaction with the enzyme. In terms of drug concentration exerting 50% inhibition of ergosterol biosynthesis, NND-502 was 2.5 and 28 times more effective than that of lanoconazole and bifonazole, respectively.
Niwano
Y
Y
Research Center, Nihon Nohyaku Co, Ltd, Kawachinagao, Osaka, Japan. nntoxlab@os.luice.or.jp
Koga
H
H
Kodama
H
H
Kanai
K
K
Miyazaki
T
T
Yamaguchi
H
H
D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D065607:Cytochrome P-450 Enzyme Inhibitors; D004875:Ergosterol / Q000096:biosynthesis*; D007093:Imidazoles / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D058886:Sterol 14-Demethylase
D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; C112528:luliconazole; D004875:Ergosterol