title: Syntheses, cholinesterases inhibition, and molecular docking studies of pyrido[2,3-b]pyrazine derivatives.
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.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Hameed
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
authors.forename: Syeda T
authors.initials: ST
authors.lastname: Zehra
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan.
authors.forename: Syed J A
authors.initials: SJ
authors.lastname: Shah
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Khan
authors.affiliation: Department of Chemistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Rima D
authors.initials: RD
authors.lastname: Alharthy
authors.affiliation: 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.
authors.forename: Norbert
authors.initials: N
authors.lastname: Furtmann
authors.affiliation: 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.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
authors.affiliation: Department of Physics, University of Sargodha, Sargodha, Pakistan.
authors.forename: Muhammad N
authors.initials: MN
authors.lastname: Tahir
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan.
authors.forename: Jamshed
authors.initials: J
authors.lastname: Iqbal
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D011719:Pyrazines; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: acetophenone derivatives; acetylcholinesterase; butyrylcholinesterase; cholinesterases; diaminopyridine; pyrido[2,3-b]pyrazines