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Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes.
Eur J Med Chem. 2016 Nov 29; 124:1026-1040.EJ

Abstract

Donepezil (DNP), an acetylcholinesterase (AChE) inhibitor, is one of the most preferred choices in Alzheimer diseases (AD) therapy. In the present study, 38 new DNP analogues were synthesized. Structures of the synthesized compounds (1-38) were elucidated by IR, 1H NMR, 13C NMR and HRMS spectroscopic methods and elemental analysis. Inhibitory potential of the compounds on cholinesterase enzymes was investigated. None of the compounds displayed significant activity on butyrylcholinesterase (BChE) enzyme. On the other hand, compounds 26-29 indicated important inhibitory activity on AChE enzyme. Kinetic studies were performed in order to observe the effects of the most active compounds on substrate-enzyme relationship. Cytotoxicity studies and theoretical calculation of pharmacokinetic properties were also carried out to get an information about toxicity and pharmacokinetic profiles of the compounds. The compounds 26-29 were found to be nontoxic at their effective concentrations against AChE. A good pharmacokinetic profile was predicted for these compounds. Docking studies were performed for the most active compounds 26-29 and interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds.

Authors+Show Affiliations

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey; Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey.Department of Toxicology, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey; Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey. Electronic address: yozkay@anadolu.edu.tr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27783974

Citation

Sağlık, Begüm Nurpelin, et al. "Synthesis of New Donepezil Analogues and Investigation of Their Effects On Cholinesterase Enzymes." European Journal of Medicinal Chemistry, vol. 124, 2016, pp. 1026-1040.
Sağlık BN, Ilgın S, Özkay Y. Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes. Eur J Med Chem. 2016;124:1026-1040.
Sağlık, B. N., Ilgın, S., & Özkay, Y. (2016). Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes. European Journal of Medicinal Chemistry, 124, 1026-1040. https://doi.org/10.1016/j.ejmech.2016.10.042
Sağlık BN, Ilgın S, Özkay Y. Synthesis of New Donepezil Analogues and Investigation of Their Effects On Cholinesterase Enzymes. Eur J Med Chem. 2016 Nov 29;124:1026-1040. PubMed PMID: 27783974.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes. AU - Sağlık,Begüm Nurpelin, AU - Ilgın,Sinem, AU - Özkay,Yusuf, Y1 - 2016/10/19/ PY - 2016/10/07/received PY - 2016/10/17/revised PY - 2016/10/18/accepted PY - 2016/11/7/entrez PY - 2016/10/27/pubmed PY - 2017/3/1/medline KW - Acetylcholinesterase KW - Alzheimer diseases KW - Docking KW - Indanone KW - Piperazine SP - 1026 EP - 1040 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 124 N2 - Donepezil (DNP), an acetylcholinesterase (AChE) inhibitor, is one of the most preferred choices in Alzheimer diseases (AD) therapy. In the present study, 38 new DNP analogues were synthesized. Structures of the synthesized compounds (1-38) were elucidated by IR, 1H NMR, 13C NMR and HRMS spectroscopic methods and elemental analysis. Inhibitory potential of the compounds on cholinesterase enzymes was investigated. None of the compounds displayed significant activity on butyrylcholinesterase (BChE) enzyme. On the other hand, compounds 26-29 indicated important inhibitory activity on AChE enzyme. Kinetic studies were performed in order to observe the effects of the most active compounds on substrate-enzyme relationship. Cytotoxicity studies and theoretical calculation of pharmacokinetic properties were also carried out to get an information about toxicity and pharmacokinetic profiles of the compounds. The compounds 26-29 were found to be nontoxic at their effective concentrations against AChE. A good pharmacokinetic profile was predicted for these compounds. Docking studies were performed for the most active compounds 26-29 and interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/27783974/Synthesis_of_new_donepezil_analogues_and_investigation_of_their_effects_on_cholinesterase_enzymes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(16)30904-7 DB - PRIME DP - Unbound Medicine ER -