N-acyloxymethyl carbamate linked prodrugs of pseudomycins are novel antifungal agents. |
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Authors: | X Sun D J Zeckner W L Current R Boyer C McMillian N Yumibe S H Chen |
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Institution: | Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, 46285, Indianapolis, IN, USA. |
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Abstract: | 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. |
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