Multifunctional hybrid sulfonamides as novel therapeutic agents for Alzheimer's disease

Future Med Chem. 2019 Dec;11(24):3161-3178. doi: 10.4155/fmc-2019-0106.

Abstract

Aim: A breakthrough in modern medicine, in terms of treatment of Alzheimer's disease, is yet to be seen, as the scene is currently plagued with numerous clinical trial failures. Here, we are exploring multifunctional hybrid sulfonamides for their anti-Alzheimer activity due to the complex nature of the disease. Results & methodology: Compound 41 showed significant inhibition of MMP-2 (IC50: 18.24 ± 1.62 nM), AChE (IC50: 4.28 ± 0.15 μM) and BuChE (IC50: 1.32 ± 0.02 μM). It also exhibited a metal-chelating property, as validated by an in vitro metal-induced Aβ aggregation assay using confocal fluorescence imaging. Whereas, MTT and DPPH assays revealed it to be nontoxic and neuroprotective with substantial antioxidant property. Conclusion: The present study puts forth potent yet nontoxic lead molecules, which foray into the field of multitargeted agents for the treatment of Alzheimer's disease.

Keywords: Alzheimer’s disease; acetylcholine esterase; amyloid β; butyrylcholinesterase; confocal fluorescence microscopy; matrix metalloproteinase-2; metal chelation; β-alanine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Animals
  • Butyrylcholinesterase / metabolism
  • Cell Survival / drug effects
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacokinetics
  • Chelating Agents / therapeutic use*
  • Chlorocebus aethiops
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacokinetics
  • Cholinesterase Inhibitors / therapeutic use*
  • Computer Simulation
  • Disease Models, Animal
  • Humans
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase Inhibitors / chemistry
  • Matrix Metalloproteinase Inhibitors / pharmacokinetics
  • Matrix Metalloproteinase Inhibitors / therapeutic use*
  • Maze Learning / drug effects
  • Molecular Docking Simulation
  • Molecular Structure
  • Rats
  • Rats, Wistar
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / therapeutic use*
  • Vero Cells

Substances

  • Amyloid beta-Peptides
  • Chelating Agents
  • Cholinesterase Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Sulfonamides
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • MMP2 protein, human
  • Matrix Metalloproteinase 2