title: Coumarin derivatives as potential inhibitors of acetylcholinesterase: Synthesis, molecular docking and biological studies.
abstract: A series of novel hybrids has been synthesized by linking coumarin moiety through an appropriate spacer to various substituted heterocyclic amines and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of cognitive dysfunction caused by increased hydrolysis of acetylcholine and scopolamine induced oxidative stress. Anti-amnesic activity of the compounds was evaluated using Morris water maze model at a dose of 1mg/kg with reference to the standard, donepezil. Biochemical estimation of oxidative stress markers (lipid peroxidation, superoxide dismutase, and plasma nitrite) was carried out to assess the antioxidant potential of the synthesized molecules. Among all the synthesized compounds (15a-i, 16a-d, 17a-b), compound 15a [4-[3-(4-phenylpiperazin-1-yl)propoxy]-2H-chromen-2-one] displayed significant antiamnesic activity, AChE inhibitory activity (IC50=2.42μM) and antioxidant activity in comparison to donepezil (IC50=1.82μM). Molecular docking study of 15a indicated that it interacts with all the crucial amino acids present at the CAS, mid-gorge and PAS of TcAChE resulting in increased inhibition of AChE enzyme.
authors: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.
authors: Shaffali
authors: S
authors: Singla
authors: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India. Electronic address: ppvohra28in@yahoo.co.in.
authors: Poonam
authors: P
authors: Piplani
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000647:Amnesia / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D018384:Oxidative Stress / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D003374:Coumarins; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase inhibition; Cognitive dysfunction; Coumarin moiety; Heterocyclic amines; Morris water maze; Oxidative stress