Mahmoud W.R.Nissan Y.M.Elsawah M.M.Refaey R.H.Ragab M.F.Amin K.M.Pharmaceutical Chemistry DepartmentFaculty of PharmacyCairo UniversityKasr Elini StCairo11562Egypt; Pharmaceutical Chemistry DepartmentFaculty of PharmacyOctober University for Modern Sciences and Arts (MSA)GizaEgypt; Drug Research CenterCairoEgypt; Pharmacology and Toxicology DepartmentFaculty of PharmacyOctober University for Modern Sciences and Arts (MSA)GizaEgypt2020-01-092020-01-0920192235234https://doi.org/10.1016/j.ejmech.2019.111651PubMed ID 31479975https://t.ly/LXMJAScopusTwenty four 6-aminocoumarin based derivatives were synthesized according to two schemes. All the compounds were screened for their acetylcholinesterase inhibitory activity where compound 5b proved to be the most potent AChE inhibitor with (IC50 = 37 nM) compared to tacrine and donepezil (IC50 = 55.0 and 59.0 nM, respectively). Six compounds 2f, 2g, 4b, 5b, 8b and 9b revealed superior activity over donepezil and a conclusive structure activity relationship study was conducted explaining the obtained results. Furthermore, compounds 2f, 4b and 5b were investigated for their neurobehavioral effect in vivo. All the tested compounds showed improvement of neurobehavioral experiments using donepezil as reference drug. In addition, compounds 2f, 4b and 5b were able to reduce extracellular deposition of amyloid beta 42 in a comparable manner to donepezil. The binding modes of the synthesized compounds were evaluated in silico via molecular docking in the active site of AChE, as well as molecular dynamics simulation study. A pharmacophore model was generated for the newly synthesized compounds. � 2019 Elsevier Masson SASEnglishAcetylcholinesterase inhibitorsAlzheimer's diseaseCoumarin derivatives2 (4 fluorophenyl) 3 (2 oxo 2h chromen 6 yl)thiazolidin 4 one2 (4 methoxyphenyl) 3 (2 oxo 2h chromen 6 yl)thiazolidin 4 one2 [(2 oxo 2h chromen 6 yl)amino] n phenylacetamide2 [4 (methylthio)phenyl] 3 (2 oxo 2h chromen 6 yl)thiazolidin 4 one5 (4 bromrobenzylidene) 2 [(2 oxo 2h chromen 6 yl)imino]thiazolidin 4 one5 (4 chlorobenzylidene) 2 [(2 oxo 2h chromen 6 yl)imino]thiazolidin 4 one5 (4 fluorobenzylidene) 2 [(2 oxo 2h chromen 6 yl)imino]thiazolidin 4 one5 (4 methoxybenzylidene) 2 [(2 oxo 2h chromen 6 yl)imino]thiazolidin 4 one5 benzylidene 2 [(2 oxo 2h chromen 6 yl)imino]thiazolidin 4 one5 [4 (dimethylamino)benzylidene] 2 [(2 oxo 2h chromen 6 yl)imino]thiazolidin 4 one5 [4 (methylthio)benzylidene] 2 [(2 oxo 2h chromen 6 yl)imino]thiazolidin 4 one6 (benzylideneamino) 2h chromen 2 one6 [(2 morpholino 2 oxoethyl)amino] 2h chromen 2 one6 [(2 oxo 2 phenylethyl)amino] 2h chromen 2 one6 [(4 bromobenzylidene)amino] 2h chromen 2 one6 [(4 chlorobenzylidene)amino] 2h chromen 2 on6 [(4 flurobenzylidene)amino] 2h chromen 2 one6 [(4 methoxybenzylidene)amino] 2h chromen 2 one6 [[2 (4 methoxyphenyl) 2 oxo ethyl]amino) 2h chromen 2 one6 [[2 oxo 2 (4 phenylpiperazin 1 yl)ethyl]amino] 2h chromen 2 one6 [[4 (dimethylamino)benzylidene]amino] 2h chromen 2 one6 [[4 (methylthio)benzylidene]amino] 2h chromen 2 oneacetylcholinesterasecholinesterase inhibitorcoumarin derivativedonepeziln (4 fluorophenyl) 2 [(2 oxo 2h chromen 6 yl)amino]acetamiden (4 methoxyphenyl) 2 [(2 oxo 2h chromen 6 yl)amino]acetamidenootropic agenttacrineunclassified drugacetylcholinesterasecholinesterase inhibitorcoumarin derivativeadultAlzheimer diseaseanimal experimentanimal modelanimal tissueArticlecognitioncomputer modelcontrolled studydrug synthesisenzyme activityenzyme inhibitionescape latencyIC50in vivo studymalememory consolidationmolecular dockingmolecular dynamicsMorris water maze testmousenonhumannovel object recognition testpharmacophorespatial memorystructure activity relationY-maze testanimalchemical structurechemistrydose responsemetabolismsynthesisAcetylcholinesteraseAnimalsCholinesterase InhibitorsCoumarinsDose-Response Relationship, DrugMaleMiceMolecular Docking SimulationMolecular StructureStructure-Activity RelationshipArticlehttps://doi.org/10.1016/j.ejmech.2019.111651PubMed ID 31479975