Carbamate derivatives of indolines as cholinesterase inhibitors and antioxidants for the treatment of Alzheimer's disease.
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| 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.
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| Authors | Inessa Yanovsky, Efrat Finkin-Groner, Andrey Zaikin, Lena Lerman, Hila Shalom, Shani Zeeli, Tehilla Weill, Isaac Ginsburg, Abraham Nudelman, Marta Weinstock |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 23 Pg. 10700-15 (Dec 13 2012) ISSN: 1520-4804 [Electronic] United States |
| PMID | 23151013 (Publication Type: Journal Article) |
| Chemical References |
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