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Synthesis and biological study of new galanthamine-peptide derivatives designed for prevention and treatment of Alzheimer’s disease

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Abstract

The Alzheimer’s disease leads to neurodegenerative processes and affecting negatively million people worldwide. The treatment of the disease is still difficult and incomplete in practice. Galanthamine is one of the most commonly used drugs against the illness. The main aim of this work is design and synthesis of new derivatives of galanthamine comprising peptide moiety as well as study of their β-secretase inhibitory activity and the anti-aggregating effect. All new derivatives of galanthamine containing analogues of Leu-Val-Phe-Phe (Aβ17-Aβ20) were synthesized in solution using fragment and consecutive condensation approaches. The new derivatives were characterized by melting points, NMR, and HPLC/MS. They were tested in vitro for β-secretase inhibition activity by means of fluorescent method and were investigated in vitro for anti-aggregation activity on sheep platelet-rich plasma. Although the new compounds do not contain a structural element responsible for the β-secretase inhibition, five of them show high or good β-secretase inhibitory activity between 19.98 and 51.19% with IC50 between 1.95 and 5.26 nM. Four of the new molecules were able to inhibit platelet aggregation between 55.0 and 90.0% with IC50 between 0.69 and 1.36 µM. Four of the compounds were able to inhibit platelet aggregation and two of them have high anti-aggregating effects.

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Abbreviations

AD:

Alzheimer’s disease

AcChE:

Acetylcholine esterase

BuChE:

Butyrylcholine esterase

Gal:

Galanthamine

NorGal:

Norgalanthamine

LD50 :

Lethal dose, 50%

PPP:

Platelet poor plasma

PRP:

Platelet-rich plasma

ADP:

Adenosine diphosphate

ATP:

Adenosine triphosphate

β-APP:

β-Amyloid precursor protein

Aβ:

β-Amyloid peptide

TBTU:

O-(Benzotriazolo-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate

DIPEA:

N-Ethyldiisopropylamine

BACE-1 Human:

β-Secretase 1 human recombinant

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Acknowledgements

This study is supported by the Scientific Research Fund of Bulgaria through the project DH 03/8, “Galanthamine’s and 4-aminopyridine’s derivatives containing peptide motif with expected effect on the Alzheimer’s disease and multiple sclerosis”. The work is also realized as a part of National Program “EUROPEAN SCIENTIFIC NETWORKS” of Ministry of Science and Education of Bulgaria, project “Drug molecule” D01-278/05.10.2020.

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Authors and Affiliations

  1. University of Chemical Technology and Metallurgy, Sofia, 1756, Bulgaria

    Lyubomir T. Vezenkov, Dancho L. Danalev, Iwan Iwanov & Veronika Karadjova

  2. Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, 1000, Bulgaria

    Valentin Lozanov

  3. Medical Faculty, Trakia University, Stara Zagora, 6000, Bulgaria

    Atanas Atanasov & Rumyana Todorova

  4. Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia, 1113, Bulgaria

    Nikolay Vassilev

Authors
  1. Lyubomir T. Vezenkov
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  4. Valentin Lozanov
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  7. Nikolay Vassilev
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  8. Veronika Karadjova
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Correspondence to Dancho L. Danalev.

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The studies were approved by the Bulgarian Food Safety Agency (187, valid until 05. 02. 2003).

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No humans were used in this research. All animals research procedures followed were in accordance with the standards set forth in the eighth edition of Guide for the Care and Use of Laboratory Animals published by the National Academies Press, Washington, D.C.)

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Vezenkov, L.T., Danalev, D.L., Iwanov, I. et al. Synthesis and biological study of new galanthamine-peptide derivatives designed for prevention and treatment of Alzheimer’s disease. Amino Acids 54, 897–910 (2022). https://doi.org/10.1007/s00726-022-03167-z

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