Discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors: novel sulfamoylcarbamates and sulfamides derived from acetophenones

Bioorg Med Chem. 2015 Jul 1;23(13):3592-602. doi: 10.1016/j.bmc.2015.04.019. Epub 2015 Apr 14.

Abstract

In this study, several novel sulfamides were synthesized and evaluated for their acetylcholine esterase (AChE) and human carbonic anhydrase I, and II isoenzymes (hCA I and II) inhibition profiles. Reductive amination of methoxyacetophenones was used for the synthesis of amines. Amines were converted to sulfamoylcarbamates with chlorosulfonyl isocyanate (CSI) in the presence of BnOH. Pd-C catalyzed hydrogenolysis of sulfamoylcarbamates afforded sulfamides. These novel compounds were good inhibitors of the cytosolic hCA I, and hCA II with Ki values in the range of 45.9±8.9-687.5±84.3 pM for hCA I, and 48.80±8.2-672.2±71.9pM for hCA II. The inhibitory effects of the synthesized novel compounds on AChE were also investigated. The Ki values of these compounds were in the range of 4.52±0.61-38.28±6.84pM for AChE. These results show that hCA I, II, and AChE were effectively inhibited by the novel sulfamoylcarbamates 17-21 and sulfamide derivatives 22-26. All investigated compounds were docked within the active sites of the corresponding enzymes revealing the reasons of the effective inhibitory activity.

Keywords: Acetylcholine esterase; Carbonic anhydrase; Enzyme inhibition; Hybrid molecules; Molecular docking; Sulfamide; Sulfamoylcarbamate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / chemistry*
  • Acetylcholinesterase / chemistry*
  • Amination
  • Carbonic Anhydrase I / antagonists & inhibitors*
  • Carbonic Anhydrase I / chemistry
  • Carbonic Anhydrase II / antagonists & inhibitors*
  • Carbonic Anhydrase II / chemistry
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry*
  • Humans
  • Isocyanates
  • Kinetics
  • Molecular Docking Simulation
  • Molecular Structure
  • Oxidation-Reduction
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*

Substances

  • Acetophenones
  • Carbonic Anhydrase Inhibitors
  • Cholinesterase Inhibitors
  • Isocyanates
  • Sulfonamides
  • chlorosulfonyl isocyanate
  • Acetylcholinesterase
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II