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Bioorg Med Chem. 2015 Sep 1;23(17):5610-8. doi: 10.1016/j.bmc.2015.07.029. Epub 2015 Jul 21.

Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

Author information

1
Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Medyczna 9, Poland. Electronic address: marek.bajda@uj.edu.pl.
2
Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Medyczna 9, Poland.
3
Laboratory of Radiopharmacy, Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, 90-151 Łódź, Muszyńskiego 1, Poland.
4
Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, 90-151 Łódź, Muszyńskiego 1, Poland.
5
Department of Medicinal Chemistry, Pharmaceutical Faculty, Medical University of Lublin, 20-090 Lublin, Jaczewskiego 4, Poland.
6
Laboratory of Radiopharmacy, Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, 90-151 Łódź, Muszyńskiego 1, Poland. Electronic address: pawel.szymanski@umed.lodz.pl.

Abstract

A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 4-dimethylaminobenzoic acid moiety was synthesized and tested towards inhibition of cholinesterases and amyloid β aggregation. Target compounds were designed as dual binding site cholinesterase inhibitors able to bind to both the catalytic and the peripheral site of the enzyme and therefore potentially endowed with other properties. The obtained derivatives were very potent inhibitors of both cholinesterases (EeAChE, EqBChE) with IC50 values ranging from sub-nanomolar to nanomolar range, and the inhibitory potency of the most promising agents was higher than that of the reference drugs (rivastigmine and tacrine). The kinetic studies of the most active compound 3a revealed competitive type of AChE inhibition. Moreover, all target compounds were more potent inhibitors of human AChE than tacrine with the most active compound 3b (IC50 = 19 nM). Compound 3a was also tested and displayed inhibitory potency against AChE-induced Aβ 1-42 aggregation (80.6% and 91.3% at 50 μM and 100 μM screening concentration, respectively). Moreover, cytotoxicity assay performed on A549 cells did not indicate toxicity of this agent. Compound 3a is a promising candidate for further development of novel multi-functional agents in the therapy of AD.

KEYWORDS:

Acetylcholinesterase inhibitors; Alzheimer’s disease; Inhibitors of Aβ aggregation; Molecular modeling; Multifunctional ligands; Tetrahydroacridines

PMID:
26242241
DOI:
10.1016/j.bmc.2015.07.029
[Indexed for MEDLINE]

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