title: Design, synthesis and biological evaluation of selected 3-[3-(amino) propoxy] benzenamines as acetylcholinesterase inhibitors.
abstract: The present paper describes design, synthesis, and biological evaluation of a series of some 3-[3-(amino)propoxy]benzenamines as acetylcholinesterase inhibitors using mice as a model and piracetam as a reference drug. The structures of these compounds were confirmed by spectral analysis and compounds were tested for memory enhancing activity using elevated plus maze test and acetylcholinesterase inhibitory assay. The inhibitory range of synthesized compounds was from 8.99 to 28.31 μM. The synthesized compounds possessed higher or equivalent percent retention as compared to piracetam at 1 mg/kg with no other CNS-related activities (locomotor and muscle relaxant, analgesic and anticonvulsant activities). Compound 3-[3-(imidazolo)propoxy]benzenamine has shown significant dose-dependent (1 and 3 mg/kg) memory enhancing activity, while 3-[3-(pyrrolidino)propoxy]benzenamine also showed activity equivalent to reference drug piracetam at 1 mg/kg. Both compounds 3-[3-(pyrrolidino)propoxy]benzenamine and 3-[3-(imidazolo)propoxy]benzenamine were also found to show AChE inhibition with IC50value of 8.99 and 17.87 μM. The molecular docking, MM-GBSA and molecular dynamics simulation studies were performed in order to establish a relationship between the biological results. RMSD, root-mean-square fluctuations, and interaction patterns of 10a-AChE and Sck-AChE complexes proved that the binding affinity of 10a toward AChE was highly stable with the proposed binding orientations.
authors.affiliation: a Department of Pharmacy , School of Chemical Sciences and Pharmacy, Central University of Rajasthan , Bandarsindri, Kishangarh, Ajmer 305817 , India.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Malik
authors.affiliation: b Department of Medicinal and Pharmaceutical Chemistry , B.R. Nahata College of Pharmacy , Mandsaur , Madhya Pradesh 458001 , India.
authors.forename: Richa
authors.initials: R
authors.lastname: Gupta
authors.affiliation: a Department of Pharmacy , School of Chemical Sciences and Pharmacy, Central University of Rajasthan , Bandarsindri, Kishangarh, Ajmer 305817 , India.
authors.forename: Shubham
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: a Department of Pharmacy , School of Chemical Sciences and Pharmacy, Central University of Rajasthan , Bandarsindri, Kishangarh, Ajmer 305817 , India.
authors.forename: Bhanwar Singh
authors.initials: BS
authors.lastname: Choudhary
authors.affiliation: c School of Pharmacy, MM University , Sadopur, Ambala , Haryana 134007 , India.
authors.forename: Manish
authors.initials: M
authors.lastname: Sharma
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D055162:Biocatalysis; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D001555:Benzene Derivatives; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase
keywords: Alzheimer’s disease; acetylcholinesterase inhibitors; docking; memory enhancers; molecular dynamics