Design, Synthesis, and Biological Evaluation of Novel Fluorinated Ethanolamines

• Published in: Chemistry : a European journal 2011-12, Vol.17 (52), p.14772-14784
• Main Authors: Fustero, Santos, Cuñat, Ana C., Flores, Sonia, Báez, Claribel, Oliver, Judit, Cynamon, Michael, Gütschow, Michael, Mertens, Matthias D., Delgado, Oscar, Tresadern, Gary, Trabanco, Andrés A.
• Format: Article
• Language: English
• Subjects: Amyloid Precursor Protein Secretases - chemistry; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Antiinfectives and antibacterials; antimicrobials; Aspartic Acid Endopeptidases - chemistry; BACE1; Biological; Chemistry; Derivatives; Epoxy Compounds - chemical synthesis; Epoxy Compounds - chemistry; Epoxy Compounds - pharmacology; Ethanolamine - chemical synthesis; Ethanolamine - chemistry; ethanolamines; Fluorination; fluorine; Halogenation; Humans; Imines; Imines - chemical synthesis; Imines - chemistry; Molecular Structure; Mycobacterium - drug effects; Nocardia - drug effects; peptidomimetics; Peptidomimetics - chemistry; Phthalic Acids - chemical synthesis; Phthalic Acids - chemistry; Precursors; Stereoisomerism; Strategy; Sulfonium Compounds - chemistry; Synthesis
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201102078

The preparation of novel fluorinated allylamines and their use as key fragments for the stereoselective synthesis of hydroxyethyl secondary amine (HEA)‐type peptidomimetics is described. Our strategy employs chiral sulfinyl imines as synthesis intermediates, by treatment of hemiaminal precursors with two equivalents of vinylmagnesium bromide. The subsequent oxidation of the allylic amines to the corresponding epoxides was achieved by treatment with methyl(trifluoromethyl)dioxirane. Finally, epoxide ring opening with a range of nitrogen nucleophiles provided a library of HEA‐derived peptidomimetics with a phenyldifluoromethylene moiety. The biological evaluation of these derivatives revealed compounds with remarkable BACE1 inhibitory activity. Docking studies revealed the influence of the fluorine atoms in the binding mode of the synthesized ligands. Furthermore, the biological evaluation of our final products and synthesis intermediates led to the discovery of compounds with antimicrobial activity against Mycobacterium and Nocardia species. BACE‐ically good: Stereoselective synthesis of biologically active, fluorinated, ethanolamine‐type peptidomimetics is described. Our synthesis strategy involves chiral sulfinyl imines as intermediates, by treatment of hemiaminal precursors with vinylmagnesium bromide (see scheme). The biological evaluation of the derivatives revealed compounds with remarkable BACE1 inhibitory activity as well as antimicrobial activity.