N-Acyloxymethyl carbamate linked prodrugs of pseudomycins are novel antifungal agents

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. (C) 2001 Elsevier Science Ltd. All rights reserved.