Synthesis, characterization, crystal structure of novel bis-thiomethylcyclohexanone derivatives and their inhibitory properties against some metabolic enzymes

Bioorg Chem. 2019 Feb:82:393-404. doi: 10.1016/j.bioorg.2018.11.001. Epub 2018 Nov 3.

Abstract

In this study, a series of novel bis-thiomethylcyclohexanone compounds (3a-3j) were synthesized by the addition of thio-Michael to the bis-chalcones under mild reaction conditions. The bis-thiomethylcyclohexanone derivatives (bis-sulfides) were characterized by 1H NMR, 13C NMR, FTIR and elemental analysis techniques. Furthermore, the molecular and crystal structures of 3h, 3i and 3j compounds were determined by single crystal X-ray diffraction studies. In this study, X-ray crystallography provided an alternative and often-complementary means for elucidating functional groups at the enzyme inhibitory site. Acetylcholinesterase (AChE) is a member of the hydrolase protein super family and has a significant role in acetylcholine-mediated neurotransmission. Here, we report the synthesis and determining of novel bis-thiomethylcyclohexanone compounds based hybrid scaffold of AChE inhibitors. The newly synthesized bis-thiomethylcyclohexanone compounds showed Ki values of in range of 39.14-183.23 nM against human carbonic anhydrase I isoenzyme (hCA I), 46.03-194.02 nM against human carbonic anhydrase II isoenzyme (hCA II), 4.55-32.64 nM against AChE and 12.77-37.38 nM against butyrylcholinesterase (BChE). As a result, novel bis-thiomethylcyclohexanone compounds can have promising anti Alzheimer drug potential and record novel hCA I, and hCA II enzymes inhibitor.

Keywords: Acetylcholinesterase; Bis-thiomethylcyclohexanone; Carbonic anhydrase; Crystal structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetazolamide / chemistry
  • Acetylcholinesterase / chemistry
  • Butyrylcholinesterase / chemistry
  • Carbonic Anhydrase I / antagonists & inhibitors
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry*
  • Crystallography, X-Ray
  • Cyclohexanones / chemical synthesis
  • Cyclohexanones / chemistry*
  • Humans
  • Kinetics
  • Molecular Structure
  • Sulfides / chemical synthesis
  • Sulfides / chemistry*
  • Tacrine / chemistry

Substances

  • Carbonic Anhydrase Inhibitors
  • Cholinesterase Inhibitors
  • Cyclohexanones
  • Sulfides
  • Tacrine
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II
  • Acetazolamide