Novel Pyridine-Containing Sultones: Structure-Activity Relationship and Biological Evaluation as Selective AChE Inhibitors for the Treatment of Alzheimer's disease

ChemMedChem. 2021 Oct 15;16(20):3189-3200. doi: 10.1002/cmdc.202100272. Epub 2021 Jun 22.

Abstract

Novel pyridine-containing sultones were synthesized and evaluated for their cholinesterase (ChE) inhibitory activity. Most of compounds showed selective acetylcholinesterase (AChE) inhibitory activity. The structure-activity relationship (SAR) showed: (i) the fused pyridine-containing sultones increase AChE inhibition, series B>series A; (ii) for series A, the effect of the 4-substituent on AChE activity, p->m- or o-; (iii) for series B, a halophenyl group increase activity. Compound B4 (4-(4-chlorophenyl)-2,2-dioxide-3,4,5,6-tetrahydro-1,2-oxathiino[5,6-h]quinoline) was identified as a selective AChE inhibitor (IC50 =8.93 μM), and molecular docking studies revealed a good fit into TcAChE via hydrogen interactions between the δ-pyridylsultone scaffold with Asp72, Ser122, Phe288, Phe290 and Trp84. Compound B4 showed reversible and non-competitive (Ki =7.67 μM) AChE inhibition, nontoxicity and neuroprotective activity. In vivo studies confirmed that compound B4 could ameliorate the cognitive performance of scopolamine-treated C57BL/6 J mice, suggesting a significant benefit of AChE inhibition for a disease-modifying treatment of AD.

Keywords: Acetylcholinesterase; Alzheimer's disease; SuFEx; pyridine; sultone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / chemically induced
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Animals
  • Butyrylcholinesterase / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Electrophorus
  • Horses
  • Humans
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Molecular Structure
  • Morris Water Maze Test
  • Naphthalenesulfonates / chemical synthesis
  • Naphthalenesulfonates / chemistry
  • Naphthalenesulfonates / pharmacology*
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • PC12 Cells
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Rats
  • Scopolamine / administration & dosage
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Naphthalenesulfonates
  • Neuroprotective Agents
  • Pyridines
  • naphthosultone
  • Scopolamine
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • pyridine