Abstract
With the aim of identifying safer pseudomycin derivatives, we synthesized and evaluated a number of N-acyloxymethyl carbamate linked prodrugs of 3-amido pseudomycin analogues. To our satisfaction, all of the prodrug-amide combinations prepared exhibited good in vivo efficacy against murine Candidiasis. When evaluated in a dose elevation study, all of the newly synthesized combinations (e.g., 4A, 6A, 8A, and 8B) demonstrated improved toxicity profiles in comparison to their corresponding 3-amides as well as the parent pseudomycin B.
MeSH terms
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Amides / chemistry
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Amides / pharmacology
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Animals
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Antifungal Agents / chemical synthesis
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Antifungal Agents / pharmacology*
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Antifungal Agents / toxicity
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Aspergillus fumigatus / drug effects
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Candida albicans / drug effects
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Candidiasis / drug therapy*
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Carbamates / chemistry
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Cryptococcosis / drug therapy*
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Cryptococcus neoformans / drug effects
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Disease Models, Animal
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Mice
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Microbial Sensitivity Tests
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Peptides, Cyclic / chemistry
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Peptides, Cyclic / pharmacology*
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Peptides, Cyclic / toxicity
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Prodrugs / chemical synthesis
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Prodrugs / pharmacology*
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Prodrugs / toxicity
Substances
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Amides
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Antifungal Agents
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Carbamates
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Peptides, Cyclic
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Prodrugs
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pseudomycin B
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methyl carbamate