title: Novel Tacrine-Based Pyrano[3',4':5,6]pyrano[2,3-b]quinolinones: Synthesis and Cholinesterase Inhibitory Activity.
abstract: In order to develop effective anti-cholinesterase compounds, a novel series of pyrano[3',4':5,6]pyrano[2,3-b]quinolinones were designed, synthesized, and evaluated in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All derivatives showed very good AChE inhibitory (AChEI) activity (IC50= 0.37-5.62 μM) compared with rivastigmine (IC50= 11.07 μM). Among them, 11-amino-12-(2,3-dichlorophenyl)-3-methyl-7,8,9,10-tetrahydropyrano[3',4':5,6]pyrano[2,3-b]quinolin-1(12H)-one (6f) displayed the best inhibitory activity. However, most of the synthesized compounds showed no anti-BChE activity and compounds 6b and 6f were found to be only moderate inhibitors. The most potent anti-AChE compound 6f had low and moderate inhibitory activity and neuroprotective effects against beta-secretase (BACE1) and oxidative stress-induced cell death, respectively. Also, kinetic and molecular docking studies of binding interactions elucidated that compound 6f bound to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE.
authors.affiliation: Faculty of Pharmacy, Department of Medicinal Chemistry, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Roshanak
authors.initials: R
authors.lastname: Hariri
authors.affiliation: Faculty of Pharmacy, Department of Medicinal Chemistry, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Afshar
authors.affiliation: Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Mahdavi
authors.affiliation: Department of Biotechnology, Iranian Research Organization for Science and Technology, Tehran, Iran.
authors.forename: Maliheh
authors.initials: M
authors.lastname: Safavi
authors.affiliation: Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.|Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mina
authors.initials: M
authors.lastname: Saeedi
authors.affiliation: Faculty of Pharmacy, Department of Medicinal Chemistry, Hamadan University of Medical Sciences, Hamadan, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Najafi
authors.affiliation: Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Reyhaneh
authors.initials: R
authors.lastname: Sabourian
authors.affiliation: Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Elahe
authors.initials: E
authors.lastname: Karimpour-Razkenari
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Najmeh
authors.initials: N
authors.lastname: Edraki
authors.affiliation: Department of Cellular Biotechnology at Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
authors.forename: Farshad Homayouni
authors.initials: FH
authors.lastname: Moghadam
authors.affiliation: Faculty of Pharmacy, Department of Medicinal Chemistry, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Abbas
authors.initials: A
authors.lastname: Shafiee
authors.affiliation: Faculty of Pharmacy, Department of Pharmacognosy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Khanavi
authors.affiliation: Faculty of Pharmacy, Department of Medicinal Chemistry, Tehran University of Medical Sciences, Tehran, Iran.|Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Tahmineh
authors.initials: T
authors.lastname: Akbarzadeh
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006861:Hydrogen Peroxide; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D018696:Neuroprotective Agents; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000068836:Rivastigmine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives*
chemical_list: D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D015363:Quinolones; D013619:Tacrine; D006861:Hydrogen Peroxide; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D000068836:Rivastigmine
keywords: Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Fused heterocycles; Pyrano[3’,4’:5,6]pyrano[2,3-b]quinolinones