title: Synthesis, Characterization and Cholinesterase Inhibition Studies of New Arylidene Aminothiazolylethanone Derivatives.
abstract: BACKGROUND
  Alzheimer's disease is caused by the destruction or loss of cholinergic cells that produce or use ACh in the brain, thereby reducing the availability of enzyme to other cells. The major treatment strategy for AD is to decrease the level of cholinesterase in the brain.
  
  
  OBJECTIVE
  The aim of this study was to describe the effect of novel series of thiazole derivatives i.e. arylidene aminothiazolylethanones (3a-h) as cholinesterase inhibitors (CEIs).
  
  
  METHODS
  A novel series of thiazole derivatives i.e. arylidene aminothiazolylethanones (3a-h) was synthesized by treating 3-chloropentane-2,4-dione (1) with urea followed by reaction with suitably substituted benzaldehydes. Structural confirmation of all the synthesized compounds was carried out by spectroscopic techniques (FTIR, 1H and 13CNMR) and elemental analysis. Furthermore, these derivatives were subjected to biological evaluation as potential inhibitors of cholinesterases i.e. acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).
  
  
  RESULTS
  In all synthesized compounds except two compounds i.e. 3a and 3f, all compounds were identified as selective inhibitors of AChE. Compound 3a exhibited potent inhibitory values against AChE (IC50± SEM = 1.78±0.11 µM), exhibiting ≈7 times greater selectivity for AChE over BChE. Kinetics studies were performed to find out the mechanism of inhibition against respective enzyme. In addition, molecular docking studies of most potent inhibitors were also carried out to determine the binding interactions with AChE and BChE, respectively.
  
  
  CONCLUSIONS
  In this study, novel thiazole derivatives i.e. arylidene aminothiazolylethanones were successfully synthesized, characterized and further screened for threir potential as cholinesterase inhibitors. All compounds were found as potent selective inhibitors of AChE except two compounds which exhibited dual inhibitory activities but both of these compounds were highly selective toward AChE as compared to BChE.
authors.affiliation: Department of Chemistry, Quaid-I-Azam University, 45320, Islamabad. Pakistan.
authors.forename: Pervaiz A
authors.initials: PA
authors.lastname: Channar
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060. Pakistan.
authors.forename: Muhammad S
authors.initials: MS
authors.lastname: Shah
authors.affiliation: Department of Chemistry, Quaid-I-Azam University, 45320, 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: Shafi U
authors.initials: SU
authors.lastname: Khan
authors.affiliation: Department of Chemistry, Quaid-I-Azam University, 45320, Islamabad. Pakistan.
authors.forename: Fayaz A
authors.initials: FA
authors.lastname: Larik
authors.affiliation: Department of Chemistry, Quaid-I-Azam University, 45320, Islamabad. Pakistan.
authors.forename: Ghulam
authors.initials: G
authors.lastname: Shabir
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; D002091:Butyrylcholinesterase / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D009388:Neostigmine / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D002800:Cholinesterase Inhibitors; D013844:Thiazoles; D009388:Neostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: 3-chloropentane-2; 4-dione; acetylcholinesterase (AChE); butyrylcholinesterase (BChE); mechanism of inhibition; molecular docking