Abstract
A new class of biologically active nonpeptidic inhibitors of Candida albicans NMT has been synthesized starting from the octapeptide ALYASKLS-NH2 (2). The synthetic strategy entailed the preparation of novel protected Ser-Lys mimics 9 and 12 from (S)- or (R)-3-iodotyrosine and then grafting key enzyme recognition elements in a stepwise manner. Like 2, compounds 16, 17, and 18 are competitive Candida NMT inhibitors that bind to the peptide recognition site of the enzyme. Moreover, 16-18 have an affinity comparable to that of 2 even though they are devoid of peptide bonds. In contrast to 2, these nonpeptidic inhibitors exhibit antifungal activity.
MeSH terms
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Acyltransferases / antagonists & inhibitors*
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Antifungal Agents / chemical synthesis*
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Antifungal Agents / pharmacology
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Candida albicans / drug effects
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Candida albicans / enzymology
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacology
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Stereoisomerism
Substances
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Antifungal Agents
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Enzyme Inhibitors
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Imidazoles
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N-(1-((3-(aminobutyl)-4-(cyclohexylethoxy)phenyl)methyl)-2-hydroxyethyl)-4-((2-methyl-1H-imidazol-1-yl)butyl)benzeneethanamine
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N-(1-((3-(aminopropyl)-4-(cyclohexylethoxy)phenyl)methyl)-2-hydroxyethyl)-4-((2-methyl-1H-imidazol-1-yl)butyl)benzeneethanamine
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Acyltransferases
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glycylpeptide N-tetradecanoyltransferase