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Syntheses, cholinesterases inhibition, and molecular docking studies of pyrido[2,3-b]pyrazine derivatives.
Chem Biol Drug Des. 2015 Nov; 86(5):1115-20.CB

Abstract

Cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), have a role in cholinergic deficit which evidently leads to Alzheimer's disease (AD). Inhibition of cholinesterases with small molecules is an attractive strategy in AD therapy. This study demonstrates synthesis of pyrido[2,3-b]pyrazines (6a-6q) series, their inhibitory activities against both cholinesterases, AChE and BChE, and molecular docking studies. The bioactivities data of pyrido[2,3-b]pyrazines showed 3-(3'-nitrophenyl)pyrido[2,3-b]pyrazine 6n a potent dual inhibitor among the series against both AChE and BChE with IC50 values of 0.466 ± 0.121 and 1.89 ± 0.05 μm, respectively. The analogues 3-(3'-methylphenyl)pyrido[2,3-b]pyrazine 6c and 3-(3'-fluorophenyl)pyrido[2,3-b]pyrazine 6f were found to be selective inhibition for BChE with IC50 values of 0.583 ± 0.052 μm and AChE with IC50 value of 0.899 ± 0.10 μm, respectively. Molecular docking studies of the active compounds suggested the putative binding modes with cholinesterases. The potent compounds among the series could potentially serves as good leads for the development of new cholinesterase inhibitors.

Authors+Show Affiliations

H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan.H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.Department of Chemistry, King Abdulaziz University, Jeddah, Saudi Arabia.Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmann Str. 2, D-53113, Bonn, Germany. Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany.Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmann Str. 2, D-53113, Bonn, Germany.Department of Physics, University of Sargodha, Sargodha, Pakistan.Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25951978

Citation

Hameed, Abdul, et al. "Syntheses, Cholinesterases Inhibition, and Molecular Docking Studies of Pyrido[2,3-b]pyrazine Derivatives." Chemical Biology & Drug Design, vol. 86, no. 5, 2015, pp. 1115-20.
Hameed A, Zehra ST, Shah SJ, et al. Syntheses, cholinesterases inhibition, and molecular docking studies of pyrido[2,3-b]pyrazine derivatives. Chem Biol Drug Des. 2015;86(5):1115-20.
Hameed, A., Zehra, S. T., Shah, S. J., Khan, K. M., Alharthy, R. D., Furtmann, N., Bajorath, J., Tahir, M. N., & Iqbal, J. (2015). Syntheses, cholinesterases inhibition, and molecular docking studies of pyrido[2,3-b]pyrazine derivatives. Chemical Biology & Drug Design, 86(5), 1115-20. https://doi.org/10.1111/cbdd.12579
Hameed A, et al. Syntheses, Cholinesterases Inhibition, and Molecular Docking Studies of Pyrido[2,3-b]pyrazine Derivatives. Chem Biol Drug Des. 2015;86(5):1115-20. PubMed PMID: 25951978.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Syntheses, cholinesterases inhibition, and molecular docking studies of pyrido[2,3-b]pyrazine derivatives. AU - Hameed,Abdul, AU - Zehra,Syeda T, AU - Shah,Syed J A, AU - Khan,Khalid M, AU - Alharthy,Rima D, AU - Furtmann,Norbert, AU - Bajorath,Jürgen, AU - Tahir,Muhammad N, AU - Iqbal,Jamshed, Y1 - 2015/05/28/ PY - 2015/03/01/received PY - 2015/04/17/revised PY - 2015/04/27/accepted PY - 2015/5/9/entrez PY - 2015/5/9/pubmed PY - 2016/8/2/medline KW - acetophenone derivatives KW - acetylcholinesterase KW - butyrylcholinesterase KW - cholinesterases KW - diaminopyridine KW - pyrido[2,3-b]pyrazines SP - 1115 EP - 20 JF - Chemical biology & drug design JO - Chem Biol Drug Des VL - 86 IS - 5 N2 - Cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), have a role in cholinergic deficit which evidently leads to Alzheimer's disease (AD). Inhibition of cholinesterases with small molecules is an attractive strategy in AD therapy. This study demonstrates synthesis of pyrido[2,3-b]pyrazines (6a-6q) series, their inhibitory activities against both cholinesterases, AChE and BChE, and molecular docking studies. The bioactivities data of pyrido[2,3-b]pyrazines showed 3-(3'-nitrophenyl)pyrido[2,3-b]pyrazine 6n a potent dual inhibitor among the series against both AChE and BChE with IC50 values of 0.466 ± 0.121 and 1.89 ± 0.05 μm, respectively. The analogues 3-(3'-methylphenyl)pyrido[2,3-b]pyrazine 6c and 3-(3'-fluorophenyl)pyrido[2,3-b]pyrazine 6f were found to be selective inhibition for BChE with IC50 values of 0.583 ± 0.052 μm and AChE with IC50 value of 0.899 ± 0.10 μm, respectively. Molecular docking studies of the active compounds suggested the putative binding modes with cholinesterases. The potent compounds among the series could potentially serves as good leads for the development of new cholinesterase inhibitors. SN - 1747-0285 UR - https://www.unboundmedicine.com/medline/citation/25951978/Syntheses_cholinesterases_inhibition_and_molecular_docking_studies_of_pyrido[23_b]pyrazine_derivatives_ L2 - https://doi.org/10.1111/cbdd.12579 DB - PRIME DP - Unbound Medicine ER -