New amide and diterpene alkaloids with anticholinesterase activity from Delphinium cyphoplectrum roots

• Published in: Daru 2024-06, Vol.32 (1), p.237-251
• Main Authors: Salehi, Arash, Zolfaghari, Behzad, Aghaei, Mahmoud, Sirous, Hajar, Sadeghi, Morteza, Gholami, Mohammad Reza, Reisi, Parham, Ghanadian, Mustafa
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Alkaloids; Alkaloids - chemistry; Alkaloids - isolation & purification; Alkaloids - pharmacology; Alzheimer's disease; Analysis; Animals; Biomedical and Life Sciences; Biomedicine; Choline; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Chromatography; Delphinium - chemistry; Diterpene Alkaloids - chemistry; Diterpenes - chemistry; Diterpenes - isolation & purification; Diterpenes - pharmacology; Drug discovery; Enzymes; Epoxy resins; Force and energy; Medicinal Chemistry; Molecular Docking Simulation; Nervous system; Nervous system diseases; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Plant Extracts - chemistry; Plant Extracts - pharmacology; Plant Roots - chemistry; Research Article; Rivastigmine
• ISSN: 2008-2231; 1560-8115; 2008-2231
• DOI: 10.1007/s40199-024-00509-y

Background The cholinergic hypothesis posits a robust correlation between the onset of Alzheimer’s disease and a pronounced deficit in acetylcholine, a pivotal neurotransmitter crucial for the central cholinergic nervous system’s function, pivotal for memory and learning. Diterpene alkaloids exhibit intricate and distinctive chemical structures that facilitate their passage through the blood-brain barrier. Moreover, their potent pharmacological attributes render them promising candidates for addressing central nervous system disorders. Objectives This investigation aims to scrutinize the alkaloidal composition of Delphinium cyphoplectrum (Ranunculaceae) roots, further exploring their anticholinesterase inhibitory activity and mode of inhibition. Method Innovative chromatography techniques were repetitively employed to purify the alkaloids. Acetylcholinesterase (AChE) inhibition assays were conducted using Ellman’s tests. The mode of inhibition was meticulously characterized through Michaelis-Menten, and Lineweaver-Burk plots. Conducting molecular docking studies, we employed the AUTO DOCK 4.2 software package. Results Eight alkaloids were identified including five C19-diterpene alkaloids (6,14,16,18-tetramethoxy-1,7,8-trihydroxy-4-methylaconitane ( 1 ), 6,16,18-trimethoxy-1,7,8,14-tetrahydroxy-4-methylaconitane ( 2 ), 6,8,16,18-tetramethoxy-1,7,14-trihydroxy-4-methylaconitane ( 3 ), 6,14,16-trimethoxy-1,7,8,18-tetrahydroxy-4-methylaconitane ( 4 ), and 14- O -acetyl-8,16-dimethoxy-1,6,7,18-tetrahydroxy-4-methylaconitane ( 5 )), an epoxy C18-diterpene alkaloid (6,8,16-trimethoxy-1,7,14-trihydroxy-3,4-epoxyaconitane ( 6 )), a known (pyrrolidin-2-one ( 7 ) and an undescribed amide alkaloid (1-(2’-hydroxylethylamine)-3,5,5,-trimethyl-1,5-dihydro-2H-pyrrol-2-one ( 8 ). All diterpene alkaloids underwent assessment for acetylcholinesterase (AChE) inhibition assay and displayed noteworthy AChE activity, surpassing that of the reference drug (with IC 50 values of 13.7, 21.8, 23.4, 28.2, 40.4, and 23.9 for compounds 1 – 6 , respectively, in comparison to 98.4 for Rivastigmine). Analysis of Michaelis-Menten and Lineweaver-Burk plots represents an uncompetitive mode of inhibition for compound 1 on AChE. Notably, computational docking simulations indicated that all diterpene alkaloids were accommodated within the same enzymatic cleft as the reference ligand, and displaying superior free binding energy values (from − 10.32 to -8.59 Kcal.mol −1 ) in contrast to Rivastigmi