TY - JOUR
T1 - Carbamate derivatives of indolines as cholinesterase inhibitors and antioxidants for the treatment of Alzheimer's disease
AU - Yanovsky, Inessa
AU - Finkin-Groner, Efrat
AU - Zaikin, Andrey
AU - Lerman, Lena
AU - Shalom, Hila
AU - Zeeli, Shani
AU - Weill, Tehilla
AU - Ginsburg, Isaac
AU - Nudelman, Abraham
AU - Weinstock, Marta
PY - 2012/12/13
Y1 - 2012/12/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84870990188&partnerID=8YFLogxK
U2 - 10.1021/jm301411g
DO - 10.1021/jm301411g
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C2 - 23151013
AN - SCOPUS:84870990188
SN - 0022-2623
VL - 55
SP - 10700
EP - 10715
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 23
ER -