title: Synthesis and structure-activity relationship study of tacrine-based pyrano[2,3-c]pyrazoles targeting AChE/BuChE and 15-LOX.
abstract: A series of tacrine-based pyrazolo[4',3':5,6]pyrano[2,3-b]quinolines and related compounds were designed and synthesized for targeting AChE, BuChE and 15-LOX enzymes in the field of Alzheimer's disease therapy. Most of compounds showed potent activity against cholinesterases and mild potency toward 15-LOX enzyme. In particular, compounds 29, 32 and 40 displayed inhibition at nano-molar level against AChE and BuChE (IC50s = 0.005-0.08 μM), being more potent than reference drug tacrine. Moreover, compound 32 with IC50 value of 31 μM was the most potent compound against 15-LOX. The cytotoxicity assay on HepG2 cells revealed that compounds 29 and 32 showed no significant cytotoxic activity even at concentration of 50 μM. The cytotoxicity of compounds 29 and 32 was significantly less than that of tacrine at higher concentrations.
authors.affiliation: Department of Organic Chemistry and Natural Products, Chemistry and Chemical Engineering Research Center of Iran, Pajohesh Blvrd., 17th Km of Tehran Karaj Highway, P.O. Box 14335-186, Tehran, Iran.
authors.forename: Ladan
authors.initials: L
authors.lastname: Pourabdi
authors.affiliation: Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 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: Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
authors.forename: Hamid
authors.initials: H
authors.lastname: Nadri
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Moradi
authors.affiliation: Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
authors.forename: Farshad Homayouni
authors.initials: FH
authors.lastname: 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 Organic Chemistry and Natural Products, Chemistry and Chemical Engineering Research Center of Iran, Pajohesh Blvrd., 17th Km of Tehran Karaj Highway, P.O. Box 14335-186, Tehran, Iran.
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Mojtahedi
authors.affiliation: Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ismaeil
authors.initials: I
authors.lastname: Haririan
authors.affiliation: Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
authors.forename: Hamid
authors.initials: H
authors.lastname: Forootanfar
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.
authors.forename: Alieh
authors.initials: A
authors.lastname: Ameri
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: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D013619:Tacrine; D001093:Arachidonate 15-Lipoxygenase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: 15-Lipoxygenase; Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Tacrine