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Combined molecular modeling and cholinesterase inhibition studies on some natural and semisynthetic O-alkylcoumarin derivatives.
Bioorg Chem. 2019 03; 84:355-362.BC

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.

Authors+Show Affiliations

Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey. Electronic address: iorhan@gazi.edu.tr.Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey.Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, 34349 Istanbul, Turkey.Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, 34349 Istanbul, Turkey.Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo, CH, Italy. Electronic address: fepifano@unich.it.Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo, CH, Italy.Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo, CH, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30530106

Citation

Orhan, Ilkay Erdogan, et al. "Combined Molecular Modeling and Cholinesterase Inhibition Studies On some Natural and Semisynthetic O-alkylcoumarin Derivatives." Bioorganic Chemistry, vol. 84, 2019, pp. 355-362.
Orhan IE, Senol Deniz FS, Salmas RE, et al. Combined molecular modeling and cholinesterase inhibition studies on some natural and semisynthetic O-alkylcoumarin derivatives. Bioorg Chem. 2019;84:355-362.
Orhan, I. E., Senol Deniz, F. S., Salmas, R. E., Durdagi, S., Epifano, F., Genovese, S., & Fiorito, S. (2019). Combined molecular modeling and cholinesterase inhibition studies on some natural and semisynthetic O-alkylcoumarin derivatives. Bioorganic Chemistry, 84, 355-362. https://doi.org/10.1016/j.bioorg.2018.11.044
Orhan IE, et al. Combined Molecular Modeling and Cholinesterase Inhibition Studies On some Natural and Semisynthetic O-alkylcoumarin Derivatives. Bioorg Chem. 2019;84:355-362. PubMed PMID: 30530106.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combined molecular modeling and cholinesterase inhibition studies on some natural and semisynthetic O-alkylcoumarin derivatives. AU - Orhan,Ilkay Erdogan, AU - Senol Deniz,F Sezer, AU - Salmas,Ramin Ekhteiari, AU - Durdagi,Serdar, AU - Epifano,Francesco, AU - Genovese,Salvatore, AU - Fiorito,Serena, Y1 - 2018/11/26/ PY - 2018/10/10/received PY - 2018/11/21/revised PY - 2018/11/24/accepted PY - 2018/12/12/pubmed PY - 2020/1/14/medline PY - 2018/12/12/entrez KW - Butyrylcholinesterase KW - Cholinesterase KW - Coumarins KW - Enzyme inhibition KW - Molecular docking KW - Pharmacokinetic analysis SP - 355 EP - 362 JF - Bioorganic chemistry JO - Bioorg. Chem. VL - 84 N2 - 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. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/30530106/Combined_molecular_modeling_and_cholinesterase_inhibition_studies_on_some_natural_and_semisynthetic_O_alkylcoumarin_derivatives_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(18)31162-3 DB - PRIME DP - Unbound Medicine ER -