title: New tetracyclic tacrine analogs containing pyrano[2,3-c]pyrazole: efficient synthesis, biological assessment and docking simulation study.
abstract: A new series of tacrine-based acetylcholinesterase (AChE) inhibitors 7a-l were designed by replacing the benzene ring of tacrine with aryl-dihydropyrano[2,3-c]pyrazole. The poly-functionalized hybrid molecules 7a-l were efficiently synthesized through multi-component reaction and subsequent Friedländer reaction between the obtained pyrano[2,3-c]pyrazoles and cyclohexanone. Most of target compounds showed potent and selective anti-AChE activity at sub-micromolar range. The most potent compound 7h bearing a 3,4-dimethoxyphenyl group was more active than reference drug tacrine. The representative compound 7h could significantly protect neurons against oxidative stress as potent as quercetin at low concentrations. The docking study of compound 7h with AChE enzyme revealed that the (R)-enantiomer binds preferably to CAS while the (S)-enantiomer prone to be a PAS binder.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Khoobi
authors.affiliation: Chemistry and Chemical Engineering Research Center of Iran (CCERCI), P.O. BOX 14335-186, Tehran, Iran.
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Ghanoni
authors.affiliation: Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
authors.forename: Hamid
authors.initials: H
authors.lastname: Nadri
authors.affiliation: Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Moradi
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran.
authors.forename: Morteza
authors.initials: M
authors.lastname: Pirali Hamedani
authors.affiliation: Neurobiomedical Research Center, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
authors.forename: Farshad
authors.initials: F
authors.lastname: Homayouni Moghadam
authors.affiliation: Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Saeed
authors.initials: S
authors.lastname: Emami
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Vosooghi
authors.affiliation: Chemistry and Chemical Engineering Research Center of Iran (CCERCI), P.O. BOX 14335-186, Tehran, Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Zadmard
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Foroumadi
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran. Electronic address: ashafiee@ams.ac.ir.
authors.forename: Abbas
authors.initials: A
authors.lastname: Shafiee
mesh_terms: D000818:Animals; D002091:Butyrylcholinesterase / Q000097:blood; D016923:Cell Death / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004593:Electrophorus; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006736:Horses; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007700:Kinetics; D062105:Molecular Docking Simulation; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016716:PC12 Cells; D011714:Pyrans / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D018696:Neuroprotective Agents; D011714:Pyrans; D011720:Pyrazoles; D013619:Tacrine; D006861:Hydrogen Peroxide; D002091:Butyrylcholinesterase
keywords: Acetylcholinesterase; Alzheimer's disease; Docking study; Neuroprotective activity; Tacrine