SCH 39304, a broad-spectrum azole derivative, was evaluated in an experimental mouse model of blastomycosis pneumonia. Five days after being inoculated with Blastomyces dermatitidis, infected mice were treated with either oral SCH 39304, fluconazole, or intraperitoneal amphotericin B. A dose response protective effect was observed with SCH 39304 at 5 to 100 mg/kg of body weight per day, with 5 mg of SCH 39304 per kg per day providing activity similar to that of 100 mg of fluconazole per kg per day. Colony counts of yeasts in the lungs of mice sacrificed while on therapy with SCH 39304 were consistently below those of controls, and several lungs were sterile. We conclude that SCH 39304 is effective in murine blastomycosis treatment and deserves to be evaluated in the treatment of human blastomycosis.
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http://dx.doi.org/10.1128/AAC.34.5.896 | DOI Listing |
Chirality
May 2002
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Genaconazole (SCH 39304) is a potent triazole antifungal agent that is active both orally and topically. Genaconazole is a racemic mixture which contains 50% of the RR (SCH 42427) and 50% of the SS (SCH 42426) enantiomers. The RR isomer accounts for most of the antifungal activity of genaconazole.
View Article and Find Full Text PDFAntimicrob Agents Chemother
July 1997
Department of Molecular Biology and Biotechnology, Krebs Institute for Biomolecular Research, Sheffield University, United Kingdom.
We investigated the stereoselective inhibition of growth and ergosterol biosynthesis by SCH39304 in the pathogenic fungus Cryptococcus neoformans obtained from four AIDS patients who failed fluconazole therapy and compared the results to those obtained with a wild-type strain. For all strains, the MICs of the RR isomer were approximately half those of the racemate, with the SS enantiomer showing no inhibitory activity. The 50% inhibitory concentrations for in vitro ergosterol biosynthesis correlated with the MIC data, indicating stereoselective inhibition of their target P-450 enzyme, sterol 14alpha-demethylase, as the cause of this difference.
View Article and Find Full Text PDFJ Antimicrob Chemother
May 1997
Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, The University of Sheffield, UK.
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.
View Article and Find Full Text PDFFEMS Microbiol Lett
April 1997
Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, UK.
Azole antifungal compounds are important in agriculture and in the treatment of mycotic infection. The target enzyme, sterol 14 alpha-demethylase (CYP51), is inhibited through binding of triazole N-4 to the haem of this P450, as a sixth ligand together with the N-1 substituent groups interacting in some way with the apoprotein. Here we use Saccharomyces cerevisiae expression systems for the target enzyme of Candida albicans to investigate binding of enantiomers of the azole antifungal compounds SCH39304 and tetraconazole.
View Article and Find Full Text PDFBioorg Med Chem
February 1996
Research Center, Sumitomo Pharmaceuticals Co., Ltd, Osaka, Japan.
Triazole analogues which contained alkylthio or alkylsulfonyl groups where synthesized as derivatives of antifungal SM-8668 and estimated for their in vitro and in vivo activity. Derivatives having pentylthio, heptylthio or nonylthio groups showed excellent efficacy against both candidiasis and aspergillosis. Introduction of a hydrophilic group at the end of their alkyl chain made their activity stronger.
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