title: Identification of a neuroprotective and selective butyrylcholinesterase inhibitor derived from the natural alkaloid evodiamine.
abstract: Two sets of carbamates based on the natural alkaloid evodiamine were designed, synthesized and evaluated as potential butyrylcholinesterase inhibitors. Although a set of carbamates of 3-hydroxyevodiamine (10a-f) is inactive both at AChE and BChE, carbamates of 5-deoxo-3-hydroxyevodiamine (11a-f) exhibit much better potency with selectivity toward BChE. The heptyl carbamate of 5-deoxo-3-hydroxyevodiamine (11c) shows the best potency with an IC50 value of 77 nM and very good selectivity over AChE. ORAC and cell-based assays indicate 11c owns pronounced antioxidant properties with 1.75 Trolox equivalents and strong neuroprotection even from 1 μM onwards. These combined activities might enable compound 11c to be a potential candidate for treatment of Alzheimer's disease.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Guozheng
authors.initials: G
authors.lastname: Huang
authors.affiliation: Pharmaceutical Biology, Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Beata
authors.initials: B
authors.lastname: Kling
authors.affiliation: Pharmaceutical Biology, Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Fouad H
authors.initials: FH
authors.lastname: Darras
authors.affiliation: Pharmaceutical Biology, Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany. Electronic address: Michael.Decker@uni-wuerzburg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D011799:Quinazolines; C049639:evodiamine; D002091:Butyrylcholinesterase
keywords: Alzheimer's disease; Butyrylcholinesterase inhibitor; Carbamates; Evodiamine; Neuroprotection