Alzheimer’s disease (AD) is a complex and still not completely understood disorder. There are a number of processes involved in the neuropathological changes leading to the neuronal death, which is the main cause of the disease. Thus, a large number of therapeutic targets have been identified and many strategies are being pursued in search for potential anti-AD drugs. The multiple ligand approach has been applied to design and synthesize a wide variety of potential dual- and multi-acting anti-AD drugs [1]. As a continuation of our studies [2], we designed compounds with inhibitory activity against cholinesterases and β-amyloid (Aβ) aggregation as dual target ligands against AD. Several series of hybrid molecules bearing alkylamino- or arylalkylamino- groups linked by alkyl chain with heterocyclic isoindolino-1,2-dione (phthalimide) were obtained. The activity of the synthesized compounds against acetylcholinesterase (AChE from electric eels) and butyrylcholinesterase (BuChE from horse serum) was evaluated in spectrophotometric Ellman’s method. The influence of the compounds on the formation of Aβ plaques was examined in the modified Thioflavine T test.
Within the obtained compounds, series of 2-(diethyaminoalkyl)-isoindoline-1,3-dione derivatives showed selective AChE inhibition with IC₅₀ values ranging from 0.9 to 19.5 μM and weak Aβ anti-aggregation activity (micromolar concentrations). Within the arylalkylamino- series, fluorobenzylamine derivatives displayed inhibitory activities against AChE in nanomolar ranges and activity against Aβ plaque formation similar to the above series. These results support the outcome of docking studies with the compounds targeting both the catalytic and the peripheral anionic sites of cholinesterases.

1. Bajda, M.; Guzior, N.; Ignasik, M.; Malawska, B., Multi-target-directed ligands in Alzheimer’s disease treatment, Curr. Med. Chem. 18, 2011, 18(32): 4949-4975.
2. Więckowska, A.; Bajda, M.; Guzior, N.; Malawska, B., Novel alkyl- and arylcarbamate derivatives with N-benzylpiperidine and N-benzylpiperazine moieties as cholinesterases inhibitors, Eur. J. Med. Chem. 2010, 45: 5602-5611.

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/28099 must be provided.

1. Multi-target-directed ligands in design and discovery of potential drugs for Alzheimer’s disease
2. INVESTIGATIONS OF LIPOPHILICITY OF ANTICANCER-ACTIVE THIOQUINOLINE DERIVATIVES
3. SEARCHING FOR NEW INHIBITORS OF CHOLINESTERASE IN GROUP OF CARBAMATES
4. SEARCH FOR NEW ANTICONVULSANT AGENTS, DERIVATIVES OF γ-BUTYROLAC- TONE AND γ-HYDROXYBUTYRIC ACID
5. AN APPLICATION OF THE ARRAY OF LIPIDATED OLIGOPEPTIDES RESEMBLING ARTIFICIAL RECEPTORS FOR MOLECULAR RECOGNITION. THE STUDIES ON THE LIPOPHLILICITY OF SOME PIPERAZINES