Synthesis of morpholine derivatives using the Castagnoli-Cushman reaction as BACE1 inhibitors: Unexpected binding activity of cyclic thioamides

Lorenzo Calugi; Elena Lenci; Riccardo Innocenti; Andrea Trabocchi

doi:10.1016/j.bmcl.2020.127211

Synthesis of morpholine derivatives using the Castagnoli-Cushman reaction as BACE1 inhibitors: Unexpected binding activity of cyclic thioamides

Bioorg Med Chem Lett. 2020 Jul 1;30(13):127211. doi: 10.1016/j.bmcl.2020.127211. Epub 2020 Apr 24.

Authors

Lorenzo Calugi¹, Elena Lenci², Riccardo Innocenti², Andrea Trabocchi³

Affiliations

¹ Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy; NEUROFARBA Department, University of Florence, Florence, Italy.
² Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy.
³ Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy. Electronic address: andrea.trabocchi@unifi.it.

PMID: 32354570
DOI: 10.1016/j.bmcl.2020.127211

Abstract

The Castagnoli-Cushman reaction between diglycolic anhydride and imines was applied for the synthesis of morpholine derivatives containing a thioamide or an amidino group. Enzyme inhibition assays towards BACE1 revealed an unexpected role of the cyclic thioamide group in providing inhibition in the micromolar range. Molecular docking calculations showed the thioamido group interacting with catalytic aspartic acid, and calculated BBB permeability indicated this molecular scaffold as a promising hit for further optimization.

Keywords: Alzheimer’s disease; Drug discovery; Enzyme inhibition; Multicomponent reaction; Peptidomimetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / chemistry
Amyloid Precursor Protein Secretases / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / chemistry
Aspartic Acid Endopeptidases / metabolism
Catalytic Domain
Enzyme Assays
Humans
Molecular Docking Simulation
Morpholines / chemical synthesis
Morpholines / chemistry*
Morpholines / metabolism
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / metabolism
Protein Binding
Thioamides / chemical synthesis
Thioamides / chemistry*
Thioamides / metabolism

Substances

Morpholines
Protease Inhibitors
Thioamides
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human