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

Bioorg Med Chem Lett. 2001 Jul 23;11(14):1875-9. doi: 10.1016/s0960-894x(01)00333-x.

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.

MeSH terms

  • Animals
  • Antifungal Agents / chemical synthesis
  • Antifungal Agents / pharmacology*
  • Aspergillus fumigatus / drug effects
  • Biotransformation / physiology
  • Candida albicans / drug effects
  • Candidiasis / drug therapy*
  • Carbamates / chemistry
  • Cryptococcus neoformans / drug effects
  • Disease Models, Animal
  • Esterases / blood
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacology*

Substances

  • Antifungal Agents
  • Carbamates
  • Peptides, Cyclic
  • Prodrugs
  • pseudomycin B
  • pseudomycin C'
  • methyl carbamate
  • Esterases