Synthesis and nootropic activity prediction of some 4-(aminomethyl)-1-benzylpyrrolidin-2-one derivatives structurally related with nebracetam

Authors

DOI:

https://doi.org/10.15587/2519-4852.2024.310731

Keywords:

synthesis, 4-(aminomethyl)-1-benzylpyrrolidin-2-one, molecular docking, acetylcholine receptors, nootropic activity

Abstract

The aim. Search for new biologically active substances with improved nootropic parameters among analogues of 4-(aminomethyl)-1-benzylpyrrolidine-2-one (Nebracetam).

Materials and methods. The required reagents were purified using standard techniques. The elemental analysis was performed on a "Hewlett Packard" automatic analyzer M-180 company. 1H NMR spectra were recorded on Varian Gemini 400 MHz spectrometer in DMSO-d6 as a solvent. LC/MS spectra were recorded with a PE SCIEX API 150EX liquid chromatograph equipped. The Autodock 4.2 software package was used for molecular docking. The active centers of the peptides (PDB ID: 5CXV, 6PV7) was used as the biologycal targets.

Results and discussion. Basic and alternative methods (1 and 2) of obtaining were used to synthesise target analogues of 4-(aminomethyl)-1-R-benzylpyrrolidine-2-one. As a result of synthetic studies, an optimized method with an alternative method has been proposed. The advantages include reducing the duration and number of synthesis stages and avoiding the use of sodium azide, a highly toxic and hazardous substance. Molecular docking of the synthesized compounds at well-documented acetylcholine receptor sites indicates that all tested molecules will contribute to the manifestation of nootropic activity to varying degrees through cholinergic neurotransmission mechanisms. This is evidenced by the calculated docking values in relation to the muscarinic target. According to the docking results, it was found that depending on the enantiomeric configuration, the molecules formed stable complexes with the target and had characteristic binding modes both in the orthosteric site and in the extracellular vestibule (site of positive allosteric modulation of mAChR). It indicates the prospects of modifying the "nebracetam scaffold" at the phenyl fragment with halogen substituents.

Conclusions. An effective method for synthesising analogues of 4-(aminomethyl)-1-R-benzylpyrrolidin-2-ones has been developed. The molecular docking revealed potential mechanisms of nootropic action of the synthesized derivatives as potential agonists and positive allosteric modulators of the muscarinic receptor

Author Biographies

Lina Perekhoda, National University of Pharmacy

Doctor of Pharmaceutical Science, Professor, Head of Department

Department of Medicinal Chemistry

Marharyta Suleiman, National University of Pharmacy

PhD, Associate Professor

Department of Medicinal Chemistry

Illya Podolsky, National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor

Department of Medicinal Chemistry

Anton Semenets, National University of Pharmacy

PhD Student

Department of Medicinal Chemistry

Natalia Kobzar, National University of Pharmacy

PhD, Associate Professor

Department of Medicinal Chemistry

Vitaliy Yaremenko, National University of Pharmacy

PhD, Associate Professor

Department of Medicinal Chemistry

Olha Vislous, National University of Pharmacy

PhD, Associate Professor

Department of Medicinal Chemistry

Victoriya Georgiyants, National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor, Head of Department

Department of Pharmaceutical Chemistry

Sergiy Kovalenko, V. N. Karazin Kharkiv National University

Doctor of Chemical Sciences, Professor

Department of Organic Chemistry

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Synthesis and nootropic activity prediction of some 4-(aminomethyl)-1-benzylpyrrolidin-2-one derivatives structurally related with nebracetam

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Published

2024-08-30

How to Cite

Perekhoda, L., Suleiman, M., Podolsky, I., Semenets, A., Kobzar, N., Yaremenko, V., Vislous, O., Georgiyants, V., & Kovalenko, S. (2024). Synthesis and nootropic activity prediction of some 4-(aminomethyl)-1-benzylpyrrolidin-2-one derivatives structurally related with nebracetam. ScienceRise: Pharmaceutical Science, (4 (50), 23–34. https://doi.org/10.15587/2519-4852.2024.310731

Issue

No. 4 (50) (2024)

Section

Pharmaceutical Science

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Copyright (c) 2024 Lina Perekhoda, Marharyta Suleiman, Illya Podolsky, Anton Semenets, Natalia Kobzar, Vitaliy Yaremenko, Olha Vislous, Victoriya Georgiyants, Sergiy Kovalenko

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