Design and Synthesis of New Derivatives of Alkaloid Lupinine: Structural Characterization, Acetylcholinesterase Inhibition Evaluation, and Molecular Modeling Study

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.