title: Synthesis, cholinesterase inhibition and molecular modelling studies of coumarin linked thiourea derivatives.
abstract: Alzheimer's disease is among the most widespread neurodegenerative disorder. Cholinesterases (ChEs) play an indispensable role in the control of cholinergic transmission and thus the acetylcholine level in the brain is enhanced by inhibition of ChEs. Coumarin linked thiourea derivatives were designed, synthesized and evaluated biologically in order to determine their inhibitory activity against acetylcholinesterases (AChE) and butyrylcholinesterases (BChE). The synthesized derivatives of coumarin linked thiourea compounds showed potential inhibitory activity against AChE and BChE. Among all the synthesized compounds, 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(3-chlorophenyl)thiourea (2e) was the most potent inhibitor against AChE with an IC50 value of 0.04±0.01μM, while 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(2-methoxyphenyl)thiourea (2b) showed the most potent inhibitory activity with an IC50 value of 0.06±0.02μM against BChE. Molecular docking simulations were performed using the homology models of both cholinesterases in order to explore the probable binding modes of inhibitors. Results showed that the novel synthesized coumarin linked thiourea derivatives are potential candidates to develop for potent and efficacious acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors.
authors.affiliation: Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan.
authors.forename: Aamer
authors.initials: A
authors.lastname: Saeed
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
authors.forename: Sumera
authors.initials: S
authors.lastname: Zaib
authors.affiliation: Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan.
authors.forename: Saba
authors.initials: S
authors.lastname: Ashraf
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
authors.forename: Javeria
authors.initials: J
authors.lastname: Iftikhar
authors.affiliation: Structural Bioinformatics Team, Division of Structural and Synthetic Biology, Center for Life Science Technologies, RIKEN, 1-7-22 Suehiro, Yokohama, Kanagawa 230-0045, Japan; Department of Biosciences, COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Muddassar
authors.affiliation: Structural Bioinformatics Team, Division of Structural and Synthetic Biology, Center for Life Science Technologies, RIKEN, 1-7-22 Suehiro, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address: drjamshed@ciit.net.pk.
authors.forename: Jamshed
authors.initials: J
authors.lastname: Iqbal
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D003374:Coumarins; C030123:coumarin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D013890:Thiourea
keywords: Acetylcholinesterase; Alzheimer’s disease; Butyrylcholinesterase; Coumarin; Homology models; Molecular docking; Thioureas