Abstract
Modification of the C-2 position of a benzofuran derivative 6 (RO-09-4609), an N-myristoyltransferase (Nmt) inhibitor, has led us to discover antifungal agents that are active in a murine systemic candidiasis model. The drug design is based on the analysis of a crystal structure of a Candida Nmt complex with 2. The optimization has been guided by various biological evaluations including a quasi in vivo assay and pharmacokinetic analysis.
MeSH terms
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Acyltransferases / antagonists & inhibitors*
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Animals
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Antifungal Agents / chemical synthesis*
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Antifungal Agents / pharmacokinetics
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Antifungal Agents / pharmacology
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Area Under Curve
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Benzofurans / chemical synthesis
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Benzofurans / pharmacokinetics*
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Benzofurans / pharmacology
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Candida albicans / drug effects
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Candida albicans / enzymology
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Candidiasis / drug therapy
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Crystallography, X-Ray
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Disease Models, Animal
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Drug Design
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Humans
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Mice
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Protein Binding
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Rats
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Rats, Inbred F344
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Structure-Activity Relationship
Substances
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Antifungal Agents
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Benzofurans
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Acyltransferases
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glycylpeptide N-tetradecanoyltransferase