title: Carbamate derivatives of indolines as cholinesterase inhibitors and antioxidants for the treatment of Alzheimer's disease.
abstract: The cascade of events that occurs in Alzheimer's disease involving oxidative stress and the reduction in cholinergic transmission can be better addressed by multifunctional drugs than cholinesterase inhibitors alone. For this purpose, we prepared a large number of derivatives of indoline-3-propionic acids and esters. They showed scavenging activity against different radicals in solution and significant protection against cytotoxicity in cardiomyocytes and primary cultures of neuronal cells exposed to H2O2 species and serum deprivation at concentrations ranging from 1 nM to 10 μM depending on the compound. For most of the indoline-3-propionic acid derivatives, introduction of N-methyl-N-ethyl or N-methyl-N-(4-methoxyphenyl) carbamate moieties at positions 4, 6, or 7 conferred both acetyl (AChE) and butyryl (BuChE) cholinesterase inhibitory activities at similar concentrations to those that showed antioxidant activity. The most potent AChE inhibitors were 120 (3-(2-aminoethyl) indolin-4-yl ethyl(methyl)carbamate dihydrochloride) and 94 (3-(3-methoxy-3-oxopropyl)-4-(((4-methoxyphenyl)(methyl) carbamoyl)oxy)indolin-1-ium hydrochloride) with IC50s of 0.4 and 1.2 μM, respectively.
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Inessa
authors.initials: I
authors.lastname: Yanovsky
authors.forename: Efrat
authors.initials: E
authors.lastname: Finkin-Groner
authors.forename: Andrey
authors.initials: A
authors.lastname: Zaikin
authors.forename: Lena
authors.initials: L
authors.lastname: Lerman
authors.forename: Hila
authors.initials: H
authors.lastname: Shalom
authors.forename: Shani
authors.initials: S
authors.lastname: Zeeli
authors.forename: Tehilla
authors.initials: T
authors.lastname: Weill
authors.forename: Isaac
authors.initials: I
authors.lastname: Ginsburg
authors.forename: Abraham
authors.initials: A
authors.lastname: Nudelman
authors.forename: Marta
authors.initials: M
authors.lastname: Weinstock
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002645:Chickens; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D009474:Neurons / Q000187:drug effects
chemical_list: D000975:Antioxidants; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007211:Indoles