PMID- 30530106
OWN - NLM
STAT- MEDLINE
DCOM- 20200113
LR  - 20200113
IS  - 1090-2120 (Electronic)
IS  - 0045-2068 (Linking)
VI  - 84
DP  - 2019 Mar
TI  - Combined molecular modeling and cholinesterase inhibition studies on some natural 
      and semisynthetic O-alkylcoumarin derivatives.
PG  - 355-362
LID - S0045-2068(18)31162-3 [pii]
LID - 10.1016/j.bioorg.2018.11.044 [doi]
AB  - 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 microM 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, 
      IC(50) = 46.58 +/- 0.91 microM). In fact, 10 of the active coumarins showed higher 
      inhibition (IC(50) = 7.01 +/- 0.28 microM - 43.31 +/- 3.63 microM) than that of galanthamine. 
      The most active ones were revealed to be 7-styryloxycoumarin 
      (IC(50) = 7.01 +/- 0.28 microM) and 7-isopentenyloxy-4-methylcoumarin 
      (IC(50) = 8.18 +/- 0.74 microM). 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.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Orhan, Ilkay Erdogan
AU  - Orhan IE
AD  - Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, 
      Turkey. Electronic address: iorhan@gazi.edu.tr.
FAU - Senol Deniz, F Sezer
AU  - Senol Deniz FS
AD  - Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, 
      Turkey.
FAU - Salmas, Ramin Ekhteiari
AU  - Salmas RE
AD  - Computational Biology and Molecular Simulations Laboratory, Department of 
      Biophysics, School of Medicine, Bahcesehir University, 34349 Istanbul, Turkey.
FAU - Durdagi, Serdar
AU  - Durdagi S
AD  - Computational Biology and Molecular Simulations Laboratory, Department of 
      Biophysics, School of Medicine, Bahcesehir University, 34349 Istanbul, Turkey.
FAU - Epifano, Francesco
AU  - Epifano F
AD  - Dipartimento di Farmacia, Universita "G. d'Annunzio" Chieti-Pescara, Via dei 
      Vestini 31, 66100 Chieti Scalo, CH, Italy. Electronic address: fepifano@unich.it.
FAU - Genovese, Salvatore
AU  - Genovese S
AD  - Dipartimento di Farmacia, Universita "G. d'Annunzio" Chieti-Pescara, Via dei 
      Vestini 31, 66100 Chieti Scalo, CH, Italy.
FAU - Fiorito, Serena
AU  - Fiorito S
AD  - Dipartimento di Farmacia, Universita "G. d'Annunzio" Chieti-Pescara, Via dei 
      Vestini 31, 66100 Chieti Scalo, CH, Italy.
LA  - eng
PT  - Journal Article
DEP - 20181126
PL  - United States
TA  - Bioorg Chem
JT  - Bioorganic chemistry
JID - 1303703
RN  - 0 (Cholinesterase Inhibitors)
RN  - 0 (Coumarins)
RN  - EC 3.1.1.7 (Acetylcholinesterase)
RN  - EC 3.1.1.8 (Butyrylcholinesterase)
SB  - IM
MH  - Acetylcholinesterase/*chemistry/metabolism
MH  - Binding Sites
MH  - Blood-Brain Barrier
MH  - Butyrylcholinesterase/*chemistry/metabolism
MH  - Cholinesterase Inhibitors/*chemistry/metabolism
MH  - Coumarins/*chemistry/metabolism
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Molecular Docking Simulation
MH  - Protein Binding
MH  - Quantitative Structure-Activity Relationship
OTO - NOTNLM
OT  - Butyrylcholinesterase
OT  - Cholinesterase
OT  - Coumarins
OT  - Enzyme inhibition
OT  - Molecular docking
OT  - Pharmacokinetic analysis
EDAT- 2018/12/12 06:00
MHDA- 2020/01/14 06:00
CRDT- 2018/12/12 06:00
PHST- 2018/10/10 00:00 [received]
PHST- 2018/11/21 00:00 [revised]
PHST- 2018/11/24 00:00 [accepted]
PHST- 2018/12/12 06:00 [pubmed]
PHST- 2020/01/14 06:00 [medline]
PHST- 2018/12/12 06:00 [entrez]
AID - S0045-2068(18)31162-3 [pii]
AID - 10.1016/j.bioorg.2018.11.044 [doi]
PST - ppublish
SO  - Bioorg Chem. 2019 Mar;84:355-362. doi: 10.1016/j.bioorg.2018.11.044. Epub 2018 
      Nov 26.