pseudomycin-b and Disease-Models--Animal

We describe herein the synthesis, bioconversion, antifungal activity, and preliminary toxicology evaluation of a series of N-acyloxymethyl carbamate linked triprodrugs of pseudomycins. The syntheses of these prodrugs (3-6) were achieved via simple N-acylation of PSB (1) or PSC' (2) with various prodrug linkers (7-9). As expected, upon incubation with mouse and/or human plasma, many of these prodrugs (3, 5, and 6) were converted to the parent compound within a few hours. Of particular significance, two pseudomycin triprodrugs (5 and 6) showed excellent in vivo efficacy against systemic Candidiasis without tail vein irritation being observed.

Topics: Animals; Antifungal Agents; Aspergillus fumigatus; Biotransformation; Candida albicans; Candidiasis; Carbamates; Cryptococcus neoformans; Disease Models, Animal; Esterases; Humans; Mice; Microbial Sensitivity Tests; Peptides, Cyclic; Prodrugs

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.

Topics: Amides; Animals; Antifungal Agents; Aspergillus fumigatus; Candida albicans; Candidiasis; Carbamates; Cryptococcosis; Cryptococcus neoformans; Disease Models, Animal; Mice; Microbial Sensitivity Tests; Peptides, Cyclic; Prodrugs