title: Stereoselective interaction of SCH 39304, a triazole, with sterol 14alpha-demethylase of Aspergillus fumigatus.
abstract: The inhibitory activity of SCH 39304 and its enantiomers on radial growth and on the target enzyme, sterol 14alpha-demethylase, in Aspergillus fumigatus was studied to assess the role of stereochemistry in the efficacy of the drug. SCH 39304 and the RR(+) enantiomer were active in inhibiting the growth while no inhibition in the growth was observed with the SS(-) enantiomer. The MIC of SCH 39304 for the growth was about twice that of the RR(+) enantiomer. The differences in IC50s of SCH 39304 and its enantiomers for cell-free ergosterol biosynthesis correlated with their variations in MICs and type II binding spectra indicated the SS(-) enantiomer failed to bind to microsomal P450. These results show that the difference between SS(-) and RR(+) enantiomers in interacting with the target enzyme is the cause for significant difference in the potency between these two forms.
authors.affiliation: Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, The University of Sheffield, UK.
authors.forename: K
authors.initials: K
authors.lastname: Venkateswarlu
authors.forename: S L
authors.initials: SL
authors.lastname: Kelly
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D004875:Ergosterol / Q000096:biosynthesis; D008826:Microbial Sensitivity Tests; D010088:Oxidoreductases / Q000187:drug effects*; D013237:Stereoisomerism; D058886:Sterol 14-Demethylase; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C056513:Sch 39304; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; D004875:Ergosterol