2-Substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamides as BACE1 inhibitors: Synthesis, biological evaluation and docking studies

Eur J Med Chem. 2017 Sep 8:137:462-475. doi: 10.1016/j.ejmech.2017.06.020. Epub 2017 Jun 10.

Abstract

In this work, a series of 2-substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamide derivatives were developed as β-secretase (BACE-1) inhibitors. Supported by docking study, a small library of derivatives were designed, synthesized and biologically evaluated in vitro. In addition, the selected compounds were tested with affinity (KD) towards BACE-1, blood brain barrier (BBB) permeability and cytotoxicity. The studies revealed that the most potent analog 41 (IC50 = 4.6 μM) with high predicted BBB permeability and low cellular cytotoxicity, could serve as a good lead structure for further optimization.

Keywords: Alzheimer's disease; BACE-1 inhibitors; BBB; Docking study; PAMPA; Permeability; Surface Plasmon Resonance (SPR).

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Acetamides
  • Enzyme Inhibitors
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human