Synthesis, anticholinesterase activity and molecular modeling study of novel carbamate-substituted thymol/carvacrol derivatives

KURT B. Z., Gazioglu I., Dag A., Salmas R. E., Kayik G., Durdagi S., ...More

BIOORGANIC & MEDICINAL CHEMISTRY, vol.25, no.4, pp.1352-1363, 2017 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 25 Issue: 4
  • Publication Date: 2017
  • Doi Number: 10.1016/j.bmc.2016.12.037
  • Journal Name: BIOORGANIC & MEDICINAL CHEMISTRY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.1352-1363
  • Keywords: Thymol, Carvacrol, Carbamate, Alzheimer's disease, Molecular docking, Molecular dynamics (MD) simulations, MM-PBSA, Induced fit docking (IFD), TACRINE-COUMARIN HYBRIDS, ACETYLCHOLINESTERASE INHIBITORS, CHOLINESTERASE-INHIBITORS, BIOLOGICAL EVALUATION, CARBONIC-ANHYDRASE, ESSENTIAL OIL, DESIGN, BINDING, THYMOL, BUTYRYLCHOLINESTERASE
  • Bezmialem Vakıf University Affiliated: Yes

Abstract

New thymol and carvacrol derivatives with the carbamate moiety were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. 5-isopropyl-2-methylphenyl(3-fluorophenyl)carbamate (29) was found to be the most potent AChE inhibitor with IC50 values of 2.22 mu M, and 5-isopropyl-2-methylphenyl (4-fluorophenyl)carbamate (30) exhibited the strongest inhibition against BuChE with IC50 value of 0.02 mu M. Additionally, the result of H4IIE hepatoma cell toxicity assay for compounds 18, 20, 29, 30 and 35 showed negligible cell death at 0.07-10 mu M. Moreover in order to better understand the inhibitory profiles of these molecules, molecular modeling studies were applied. Binding poses of studied compounds at the binding pockets of AChE and BuChE targets were determined. Predicted binding energies of these compounds as well as structural and dynamical profiles of molecules at the target sites were estimated using induced fit docking (IFD) algorithms and post-processing molecular dynamics (MD) simulations methods (i.e., Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approaches). (C) 2016 Elsevier Ltd. All rights reserved.