title: Design, synthesis, and biological evaluation of novel fluorinated ethanolamines.
abstract: 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.
authors: Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain. santos.fustero@uv.es
authors: Santos
authors: S
authors: Fustero
authors: Ana C
authors: AC
authors: Cuñat
authors: Sonia
authors: S
authors: Flores
authors: Claribel
authors: C
authors: Báez
authors: Judit
authors: J
authors: Oliver
authors: Michael
authors: M
authors: Cynamon
authors: Michael
authors: M
authors: Gütschow
authors: Matthias D
authors: MD
authors: Mertens
authors: Oscar
authors: O
authors: Delgado
authors: Gary
authors: G
authors: Tresadern
authors: Andrés A
authors: AA
authors: Trabanco
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry*; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019856:Ethanolamine / Q000138:chemical synthesis* / Q000737:chemistry*; D054879:Halogenation; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D009161:Mycobacterium / Q000187:drug effects*; D009615:Nocardia / Q000187:drug effects*; D057786:Peptidomimetics / Q000737:chemistry*; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013452:Sulfonium Compounds / Q000737:chemistry*
chemical_list: D000890:Anti-Infective Agents; D004852:Epoxy Compounds; D007097:Imines; D057786:Peptidomimetics; D010795:Phthalic Acids; D013452:Sulfonium Compounds; D019856:Ethanolamine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human