Design of anticandidal agents: synthesis and biological properties of analogs of polyoxin L

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Abstract
Six analogs of polyoxin L were synthesized from uridine. All of these analogs inhibited chitin synthetase from Candida albicans. Derivatization of the amine terminus of the polyoxin analogs resulted in loss of activity; analogs containing aromatic amino acid residues were the most efficient inhibitors of chitin synthetase. The concentration of tryptophanyl uracil polyoxin C, which caused 50% inhibition of chitin synthetase activity, was 1.6 .times. 10-6 M. This was virtually identical with the activity found for polyoxin D. None of the inhibitors effectively competed with the entry of (met)3 into C. albicans. All of the analogs caused severe morphological distortions of the yeast in culture; a number of analogs killed C. albicans at millimolar concentrations. Evidently, chitin synthetase inhibitors may have potential as anticandidal drugs.

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