| Abstract
| - Human transmissible neurodegenerations including Creutzfeldt−Jakob disease are unique, since they arecaused by prions, an infectious agent that replicates without nucleic acids but instead by inducing conversionof a host-resident normal prion protein to a misfolded conformational isoform. For pharmacotherapy ofthese unusual diseases, tricyclic heterocyclic compounds such as quinacrine have been considered, but withambiguous success in vivo, so far. On the basis of the synergistic antiprion effects of quinacrine andiminodibenzyl derivatives, we introduce a novel class of potential pharmaceuticals representing structuralchimeras of quinacrine and imipramine analogues. We describe the chemical synthesis and bioassays of afocused library of these compounds. The most potent target compound 2a revealed an EC50 value of 20 nMdetermined with a cell model of prion disease, thus substantially improving the antiprion efficacy of quinacrine.
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