Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists

Konecny, Jan; Misiachna, Anna; Hrabinova, Martina; Pulkrabkova, Lenka; Benkova, Marketa; Prchal, Lukas; Kucera, Tomas; Kobrlova, Tereza; Finger, Vladimir; Kolcheva, Marharyta; Kortus, Stepan; Jun, Daniel; Valko, Marian; Horak, Martin; Soukup, Ondrej; Korabecny, Jan

doi:10.3390/biom11010003

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Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists

by

Jan Konecny

^1,2,†,

Anna Misiachna

^3,4,5,†,

Martina Hrabinova

^1,2

,

Lenka Pulkrabkova

^1,2,

Marketa Benkova

²,

Lukas Prchal

²,

Tomas Kucera

^1,2

,

Tereza Kobrlova

²,

Vladimir Finger

^2,6,

Marharyta Kolcheva

^3,4,

Stepan Kortus

^3,4,

Daniel Jun

^1,2

,

Marian Valko

⁷,

Martin Horak

^3,4,

Ondrej Soukup

^1,2,*

and

Jan Korabecny

^1,2,*

¹

Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic

²

Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic

³

Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic

⁴

Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic

⁵

Department of Physiology, Faculty of Science, Charles University in Prague, Albertov 6, 128 43 Prague, Czech Republic

⁶

Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic

⁷

Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 812 37 Bratislava, Slovakia

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this paper.

Biomolecules 2021, 11(1), 3; https://doi.org/10.3390/biom11010003

Submission received: 25 November 2020 / Revised: 14 December 2020 / Accepted: 18 December 2020 / Published: 22 December 2020

(This article belongs to the Special Issue Cholinesterase Research)

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Abstract

Alzheimer’s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood–brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.

Keywords: acetylcholinesterase; Alzheimer’s disease; butyrylcholinesterase; fluorene; in vitro; in silico; multi-target directed ligands; N-methyl-d-aspartate receptor

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MDPI and ACS Style

Konecny, J.; Misiachna, A.; Hrabinova, M.; Pulkrabkova, L.; Benkova, M.; Prchal, L.; Kucera, T.; Kobrlova, T.; Finger, V.; Kolcheva, M.; et al. Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists. Biomolecules 2021, 11, 3. https://doi.org/10.3390/biom11010003

AMA Style

Konecny J, Misiachna A, Hrabinova M, Pulkrabkova L, Benkova M, Prchal L, Kucera T, Kobrlova T, Finger V, Kolcheva M, et al. Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists. Biomolecules. 2021; 11(1):3. https://doi.org/10.3390/biom11010003

Chicago/Turabian Style

Konecny, Jan, Anna Misiachna, Martina Hrabinova, Lenka Pulkrabkova, Marketa Benkova, Lukas Prchal, Tomas Kucera, Tereza Kobrlova, Vladimir Finger, Marharyta Kolcheva, and et al. 2021. "Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists" Biomolecules 11, no. 1: 3. https://doi.org/10.3390/biom11010003

APA Style

Konecny, J., Misiachna, A., Hrabinova, M., Pulkrabkova, L., Benkova, M., Prchal, L., Kucera, T., Kobrlova, T., Finger, V., Kolcheva, M., Kortus, S., Jun, D., Valko, M., Horak, M., Soukup, O., & Korabecny, J. (2021). Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists. Biomolecules, 11(1), 3. https://doi.org/10.3390/biom11010003

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Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists

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