Design and Synthesis of New Derivatives of Alkaloid Lupinine: Structural Characterization, Acetylcholinesterase Inhibition Evaluation, and Molecular Modeling Study
5 affiliations
- 1Laboratory of Synthesis of Biologically Active Substances, Institute of Organic Synthesis and Coal Chemistry, Karaganda 100008, Kazakhstan
- 2Institute of Molecular Biology and Biophysics, Timakova Str 14, Novosibirsk 630090, Russia
- 3N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russia
- 4Kizhner Research Center, Tomsk Polytechnic University, Tomsk 634050, Russia
- 5Department of Physics, Abylkas Saginov Karaganda Technical University, Karaganda 100027, Kazakhstan
Abstract
Plant alkaloids have been of great interest in drug development research. Alkaloid lupinine is of great interest because of its availability and biological activity. While several lupinine derivatives have been identified with specific biological activities, the ongoing challenge lies in the design and synthesis of novel derivatives with high specificity for additional pharmacological targets. This paper describes the synthesis of lupinine derivatives as acetylcholinesterase (AChE) inhibitors. Two approaches were proposed and implemented for the synthesis of new compounds (yields 71–90%): the CuAAC reaction of lupinyl azide with a series of prop-2-ynyl- and ethynyl-substituted alkaloid derivatives, and a copper-catalyzed one-pot three-component reaction (A3-coupling) involving 1-((prop-2-ynyloxy)methyl)octahydro-1H-quinolizine, formaldehyde, and secondary amines. The biological activity of the new compounds was evaluated using the Ellman method; the results showed that most of the synthesized substances demonstrated good or moderate inhibitory activity against acetylcholinesterase in vitro. Hybrid compounds containing lupinine and xanthine fragments (theophylline, caffeine) 11, 12, or colchicine 15, as well as the bis-lupinyl derivative 16, exhibited the highest inhibitory activity against AChE with IC50 values of 0.47, 0.035, 1.3, and 1.4 μM, respectively. The binding conformation and simultaneous interaction modes were further clarified by molecular docking studies.
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BibTeX
@article{nurmaganbetov2026design,
title = {{Design and Synthesis of New Derivatives of Alkaloid Lupinine: Structural Characterization, Acetylcholinesterase Inhibition Evaluation, and Molecular Modeling Study}},
author = {Zhangeldy S. Nurmaganbetov and Igor D. Ivanov and Oralgazy A. Nurkenov and Victor A. Savelyev and Andrey I. Khlebnikov and Dastan M. Turdybekov and Aizhan M. Kozhanova and Serik D. Fazylov and Zainulla M. Muldakhmetov and Elvira E. Shults},
journal = {Molecules},
year = {2026},
month = nov,
doi = {10.3390/molecules31213961},
url = {https://www.mdpi.com/1420-3049/31/21/3961},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Design and Synthesis of New Derivatives of Alkaloid Lupinine: Structural Characterization, Acetylcholinesterase Inhibition Evaluation, and Molecular Modeling Study
AU - Zhangeldy S. Nurmaganbetov
AU - Igor D. Ivanov
AU - Oralgazy A. Nurkenov
AU - Victor A. Savelyev
AU - Andrey I. Khlebnikov
AU - Dastan M. Turdybekov
AU - Aizhan M. Kozhanova
AU - Serik D. Fazylov
AU - Zainulla M. Muldakhmetov
AU - Elvira E. Shults
PY - 2026
DA - 2026/11/03
JO - Molecules
DO - 10.3390/molecules31213961
UR - https://www.mdpi.com/1420-3049/31/21/3961
AB - Plant alkaloids have been of great interest in drug development research. Alkaloid lupinine is of great interest because of its availability and biological activity. While several lupinine derivatives have been identified with specific biological activities, the ongoing challenge lies in the design and synthesis of novel derivatives with high specificity for additional pharmacological targets. This paper describes the synthesis of lupinine derivatives as acetylcholinesterase (AChE) inhibitors. Two approaches were proposed and implemented for the synthesis of new compounds (yields 71–90%): the CuAAC reaction of lupinyl azide with a series of prop-2-ynyl- and ethynyl-substituted alkaloid derivatives, and a copper-catalyzed one-pot three-component reaction (A3-coupling) involving 1-((prop-2-ynyloxy)methyl)octahydro-1H-quinolizine, formaldehyde, and secondary amines. The biological activity of the new compounds was evaluated using the Ellman method; the results showed that most of the synthesized substances demonstrated good or moderate inhibitory activity against acetylcholinesterase in vitro. Hybrid compounds containing lupinine and xanthine fragments (theophylline, caffeine) 11, 12, or colchicine 15, as well as the bis-lupinyl derivative 16, exhibited the highest inhibitory activity against AChE with IC50 values of 0.47, 0.035, 1.3, and 1.4 μM, respectively. The binding conformation and simultaneous interaction modes were further clarified by molecular docking studies.
SN - 1420-3049
ER -