Inhibition of Acetylcholinesterase by Novel Lupinine Derivatives
Schepetkin I.A. Nurmaganbetov Z.S. Fazylov S.D. Nurkenov O.A. Khlebnikov A.I. Seilkhanov T.M. Kishkentaeva A.S. Shults E.E. Quinn M.T.
April 2023MDPI
Molecules
2023#28Issue 8
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment due in part to a severe loss of cholinergic neurons in specific brain areas. AD is the most common type of dementia in the aging population. Although several acetylcholinesterase (AChE) inhibitors are currently available, their performance sometimes yields unexpected results. Thus, research is ongoing to find potentially therapeutic AChE inhibitory agents, both from natural and synthetic sources. Here, we synthesized 13 new lupinine triazole derivatives and evaluated them, along with 50 commercial lupinine-based esters of different carboxylic acids, for AChE inhibitory activity. The triazole derivative 15 [1S,9aR)-1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-2H-quinolizine)] exhibited the most potent AChE inhibitory activity among all 63 lupinine derivatives, and kinetic analysis demonstrated that compound 15 was a mixed-type AChE inhibitor. Molecular docking studies were performed to visualize interaction between this triazole derivative and AChE. In addition, a structure-activity relationship (SAR) model developed using linear discriminant analysis (LDA) of 11 SwissADME descriptors from the 50 lupinine esters revealed 5 key physicochemical features that allowed us to distinguish active versus non-active compounds. Thus, this SAR model could be applied for design of more potent lupinine ester-based AChE inhibitors.
acetylcholinesterase , acetylcholinesterase inhibitor , Alzheimer’s disease , ester , lupinine , molecular docking , triazole derivative
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Department of Microbiology and Cell Biology, Montana State University, Bozeman, 59717, MT, United States
Institute of Organic Synthesis and Coal Chemistry, Karaganda, 100008, Kazakhstan
School of Pharmacy, Medical University of Karaganda, Karaganda, 100012, Kazakhstan
Kizhner Research Center, Tomsk Polytechnic University, Tomsk, 634050, Russian Federation
Laboratory of Engineering Profile NMR Spectroscopy, Sh. Ualikhanov Kokshetau University, Kokshetau, 020000, Kazakhstan
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
Department of Microbiology and Cell Biology
Institute of Organic Synthesis and Coal Chemistry
School of Pharmacy
Kizhner Research Center
Laboratory of Engineering Profile NMR Spectroscopy
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry
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