title: Synthesis, anticholinesterase activity and molecular modeling study of novel carbamate-substituted thymol/carvacrol derivatives.
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 IC50values of 2.22μM, and 5-isopropyl-2-methylphenyl (4-fluorophenyl)carbamate (30) exhibited the strongest inhibition against BuChE with IC50value of 0.02μM. Additionally, the result of H4IIE hepatoma cell toxicity assay for compounds 18, 20, 29, 30 and 35 showed negligible cell death at 0.07-10μM. 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).
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093 Istanbul, Turkey.
authors.forename: Belma Zengin
authors.initials: BZ
authors.lastname: Kurt
authors.affiliation: Department of Analytical Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093 Istanbul, Turkey.
authors.forename: Isil
authors.initials: I
authors.lastname: Gazioglu
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093 Istanbul, Turkey.
authors.forename: Aydan
authors.initials: A
authors.lastname: Dag
authors.affiliation: Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.
authors.forename: Ramin Ekhteiari
authors.initials: RE
authors.lastname: Salmas
authors.affiliation: Department of Chemistry, Istanbul Technical University, Istanbul, Turkey.
authors.forename: Gülru
authors.initials: G
authors.lastname: Kayık
authors.affiliation: Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey. Electronic address: serdar.durdagi@med.bau.edu.tr.
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
authors.affiliation: Pamukova Vocational High School, Sakarya University, 54900 Sakarya, Turkey. Electronic address: fsonmez@sakarya.edu.tr.
authors.forename: Fatih
authors.initials: F
authors.lastname: Sonmez
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000081007:Cymenes; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D039821:Monoterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013943:Thymol / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D000081007:Cymenes; D039821:Monoterpenes; D013943:Thymol; C073316:carvacrol; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; Carbamate; Carvacrol; Induced fit docking (IFD); MM-PBSA; Molecular docking; Molecular dynamics (MD) simulations; Thymol