Combined molecular modeling and cholinesterase inhibition studies on some natural and semisynthetic O-alkylcoumarin derivatives

Bioorg Chem. 2019 Mar:84:355-362. doi: 10.1016/j.bioorg.2018.11.044. Epub 2018 Nov 26.

Abstract

Coumarins of synthetic or natural origins are an important chemical class exerting diverse pharmacological activities. In the present study, 26 novel O-alkylcoumarin derivatives were synthesized and have been tested at 100 µM for their in vitro inhibitory potential against acetylcholinesterase (AChE) and butyrlcholinesterase (BChE) targets which are the key enzymes playing role in the pathogenesis of Alzheimer's disease. Among the tested coumarins, none of them could inhibit AChE, whereas 12 of them exerted a marked and selective inhibition against BChE as compared to the reference (galanthamine, IC50 = 46.58 ± 0.91 µM). In fact, 10 of the active coumarins showed higher inhibition (IC50 = 7.01 ± 0.28 µM - 43.31 ± 3.63 µM) than that of galanthamine. The most active ones were revealed to be 7-styryloxycoumarin (IC50 = 7.01 ± 0.28 µM) and 7-isopentenyloxy-4-methylcoumarin (IC50 = 8.18 ± 0.74 µM). In addition to the in vitro tests, MetaCore/MetaDrug binary QSAR models and docking simulations were applied to evaluate the active compounds by ligand-based and target-driven approaches. The predicted pharmacokinetic profiles of the compounds suggested that the compounds reveal lipophilic character and permeate blood brain barrier (BBB) and the ADME models predict higher human serum protein binding percentages (>50%) for the compounds. The calculated docking scores indicated that the coumarins showing remarkable BChE inhibition possessed favorable free binding energies in interacting with the ligand-binding domain of the target. Therefore, our results disclose that O-alkylcoumarins are promising selective inhibitors of cholinesterase enzymes, particularly BChE in our case, which definitely deserve further studies.

Keywords: Butyrylcholinesterase; Cholinesterase; Coumarins; Enzyme inhibition; Molecular docking; Pharmacokinetic analysis.

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Acetylcholinesterase / metabolism
  • Binding Sites
  • Blood-Brain Barrier
  • Butyrylcholinesterase / chemistry*
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / metabolism
  • Coumarins / chemistry*
  • Coumarins / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Protein Binding
  • Quantitative Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Coumarins
  • Acetylcholinesterase
  • Butyrylcholinesterase