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Molecules 2016, 21(4), 410; doi:10.3390/molecules21040410

Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta

1
Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków 30-688, Poland
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana 1000, Slovenia
*
Author to whom correspondence should be addressed.
Academic Editors: Michael Decker and Diego Muñoz-Torrero
Received: 27 February 2016 / Revised: 17 March 2016 / Accepted: 23 March 2016 / Published: 26 March 2016
(This article belongs to the Special Issue Molecules against Alzheimer)
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Abstract

Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer’s disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention—compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM). Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE) (EeAChE IC50 = 0.76 μM, EqBuChE IC50 = 0.618 μM), and it inhibits amyloid beta aggregation (35.8% at 10 μM). Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB) was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer’s agents. View Full-Text
Keywords: cholinesterase inhibitors; molecular modelling; β-amyloid aggregation inhibitors; Alzheimer’s disease; multi-target-directed ligands (MTDL); PAMPA-BBB assay cholinesterase inhibitors; molecular modelling; β-amyloid aggregation inhibitors; Alzheimer’s disease; multi-target-directed ligands (MTDL); PAMPA-BBB assay
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Hebda, M.; Bajda, M.; Więckowska, A.; Szałaj, N.; Pasieka, A.; Panek, D.; Godyń, J.; Wichur, T.; Knez, D.; Gobec, S.; Malawska, B. Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta. Molecules 2016, 21, 410.

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