title: N-acyloxymethyl carbamate linked prodrugs of pseudomycins are novel antifungal agents.
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.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, 46285, Indianapolis, IN, USA.
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.forename: D J
authors.initials: DJ
authors.lastname: Zeckner
authors.forename: W L
authors.initials: WL
authors.lastname: Current
authors.forename: R
authors.initials: R
authors.lastname: Boyer
authors.forename: C
authors.initials: C
authors.lastname: McMillian
authors.forename: N
authors.initials: N
authors.lastname: Yumibe
authors.forename: S H
authors.initials: SH
authors.lastname: Chen
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects; D001711:Biotransformation / Q000502:physiology; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy*; D002219:Carbamates / Q000737:chemistry; D003455:Cryptococcus neoformans / Q000187:drug effects; D004195:Disease Models, Animal; D004950:Esterases / Q000097:blood; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D002219:Carbamates; D010456:Peptides, Cyclic; D011355:Prodrugs; C425223:pseudomycin B; C425226:pseudomycin C'; C036868:methyl carbamate; D004950:Esterases