Rational design and synthesis of homochiral azole antifungal agents*
Maurizio Botta, Federico Corelli, Fabrizio Manetti, Claudia Mugnaini,
and Andrea Tafi
Dipartimento Farmaco Chimico Tecnologico, Università
degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
Abstract: The first synthesis of both enantiomers of the antifungal
drug bifonazole (1a) and related imidazole compounds 1i and 5b,c is
described, starting from enantiomerically pure or enriched amines 6ad.
Construction of the imidazole ring on amines 6ad was performed
in a straightforward manner affording the final compounds in good overall
yield and with very high enantiomeric purity, as determined by enantioselective
HPLC. Biological evaluation in vitro of the single enantiomers of 1a,i
and 5b,c against different strains of Candida albicans did not show
any enantioselectivity. Finally, the pseudoreceptor modeling technique
was applied to generate a model able to explain and predict the inhibitory
activity of azole compounds against C. albicans P45014DM.
*Plenary lecture presented at the Hungarian-German-Italian-Polish
Joint Meeting on Medicinal Chemistry, Budapest, Hungary, 2 6 September
2001. Other presentations are published in this issue, pp.
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