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A new series of 2-(diethylaminoalkyl)-isoindoline-1,3-dione derivatives intended as dual binding site cholinesterase inhibitors were designed using molecular modeling and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and the formation of the β-amyloid (Aβ) plaques. For AChE inhibitory activity, the spectrophotometric method of Ellman and the electrophoretically mediated microanalysis assay were used, giving good results. Most of the synthesized compounds had AChE inhibitory activity with IC(50) values ranging from IC(50) = 0.9 to 19.5 µM and weak Aβ anti-aggregation inhibitory activity. These results support the outcome of docking studies which tested compounds targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The most promising selective AChE inhibitors are compounds 10 (IC(50) = 1.2 µM) and 11 (IC(50) = 1.1 µM), with 6-7 methylene chains, which also inhibit Aβ fibril formation.

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Design, Synthesis and Evaluation of Novel 2-(Aminoalkyl)isoindoline-1,3-dione Derivatives as Dual-Binding Site Acetylcholinesterase Inhibitors. -Most of the synthesized compounds show acetylcholinesterase (AChE) inhibitory activity with derivatives (I) as the most promising candidates, which also inhibit β-amyloid plaque formation. The results of biological evaluation are in accordance with docking studies. -(IGNASIK, M.; BAJDA, M.; GUZIOR, N.; PRINZ, M.; HOLZGRABE, U.; MALAWSKA*, B.; Arch. Pharm. (Weinheim, Ger.) 345 (2012) 7, 509-516, http://dx.doi.org/10.1002/ardp.201100423 ; Dep. Physicochem. Drug Anal., Jagiellonian Univ. Med. Coll., PL-30-688 Krakow, Pol.; Eng.) -H. Haber 43-206