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

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Abstract

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 IC50 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 Rivastigmine (-6.31 Kcal.mol−1).

Conclusion

The phytochemical analysis conducted on the roots of Delphinium cyphoplectrum yielded the identification of eight alkaloidal compounds including one C18-diterpene, five C19-diterpene, one pyrrolidine and one amide alkaloids. AChE inhibition assay and molecular simulations unveiled remarkable significant potency attributed to the C19-diterpene alkaloids by the order of 1 > 2 > 3,6 > 4 > 5. Presence of hydroxyl group on C-1, C-7, C-8, C-14, and C-18 increased the effect. The best in vitro activity was recorded for compound 1 able to bind to Asp72 in the narrow region of PAS, while interacting by pi-sigma with Phe330 at the hydrophobic region of the gorge involving the acyl and choline binding site. This observation underscores the substantial promise of this category of natural products in the realm of drug discovery for Alzheimer’s Disease, offering a compelling avenue for further research and therapeutic development.

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References

  1. Passeri E, Elkhoury K, Morsink M, Broersen K, Linder M, Tamayol A, Malaplate C, Yen FT, Arab-Tehrany E. Alzheimer’s disease: treatment strategies and their limitations. Int J Mol Sci. 2022;23: 13954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature. 2004;430:631–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Morales I, Cerda-Troncoso C, Andrade V, Maccioni RB. The natural product curcumin as a potential coadjuvant in Alzheimer’s treatment. J Alzheimer’s Dis. 2017;60:451–60.

    Article  CAS  Google Scholar 

  4. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A, Cohen-Mansfield J, Cooper C, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396:413–46.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chen ZR, Huang JB, Yang SL, Hong FF. Role of cholinergic signaling in Alzheimer’s disease. Molecules. 2022;27: 1816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shen Y, Liang WJ, Shi YN, Kennelly EJ, Zhao DK. Structural diversity, bioactivities, and biosynthesis of natural diterpenoid alkaloids†. Nat Prod Rep. 2020;37:763–96.

    Article  CAS  PubMed  Google Scholar 

  7. Salehi A, Ghanadian M, Zolfaghari B, Jassbi AR, Fattahian M, Reisi P, Csupor D, Khan IA, Ali Z. Neuropharmacological Potential of Diterpenoid Alkaloids. Pharmaceuticals. 2023;16:747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Daly JW. Nicotinic agonists, antagonists, and modulators from natural sources. Cell Mol Neurobiol. 2005;25:513–52.

    Article  CAS  PubMed  Google Scholar 

  9. Ahmad H, Ahmad S, Khan E, Shahzad A, Ali M, Tahir MN, Shaheen F, Ahmad M. Isolation, crystal structure determination and cholinesterase inhibitory potential of isotalatizidine hydrate from Delphinium denudatum. Pharm Biol. 2017;55:680–6.

    Article  CAS  PubMed  Google Scholar 

  10. Ahmad H, Ahmad S, Ali M, Latif A, Shah SAA, Naz H, ur Rahman N, Shaheen F, Wadood A, Khan HU, et al. Norditerpenoid alkaloids of Delphinium denudatum as cholinesterase inhibitors. Bioorg Chem. 2018;78:427–35.

    Article  CAS  PubMed  Google Scholar 

  11. Ahmad H, Ahmad S, Shah SAA, Latif A, Ali M, Khan FA, Tahir MN, Shaheen F, Wadood A, Ahmad M. Antioxidant and anticholinesterase potential of diterpenoid alkaloids from Aconitum Heterophyllum. Bioorg Med Chem. 2017;25:3368–76.

    Article  CAS  PubMed  Google Scholar 

  12. Nisar M, Ahmad M, Wadood N, Lodhi MA, Shaheen F, Choudhary M. I. New diterpenoid alkaloids from Aconitum Heterophyllum Wall: selective butyrylcholinestrase inhibitors. J Enzyme Inhib Med Chem. 2009;24:47–51.

  13. Ahmad H, Ahmad S, Shah SAA, Khan HU, Khan FA, Ali M, Latif A, Shaheen F, Ahmad M. Selective dual cholinesterase inhibitors from Aconitum laeve. J Asian Nat Prod Res. 2018;20:172–81.

    Article  CAS  PubMed  Google Scholar 

  14. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ. Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem. 1998;19:1639–62.

    Article  CAS  Google Scholar 

  15. Rostami M, Sirous H, Zabihollahi R, Aghasadeghi MR, Sadat SM, Namazi R, Saghaie L, Memarian HR, Fassihi A. Design, synthesis and anti-HIV-1 evaluation of a series of 5-hydroxypyridine-4-one derivatives as possible integrase inhibitors. Med Chem Res. 2015;24:4113–27.

    Article  CAS  Google Scholar 

  16. Gasteiger J, Marsili M. Iterative partial equalization of orbital electronegativity-a rapid access to atomic charges. Tetrahedron. 1980;36:3219–28.

    Article  CAS  Google Scholar 

  17. Morris GM, Huey R, Olson AJ. UNIT using AutoDock for ligand-receptor docking. Curr Protoc Bioinforma. 2008;24:8–14.

    Article  Google Scholar 

  18. Mamedov SD, Khalilov AD, Guseinova MK. Crystal and molecular structure of 2,2,6,6-tetramethylpiperidine-1-iminoxyl-4-(N-2-hydroxy-1-naphthaldehydeimine). J Struct Chem. 1974;15:89–94.

    Article  Google Scholar 

  19. Markwood LN. The isolation and properties of the alkaloids and oil of Larkspur seed (Delphinium Consolida). J Frankl Inst. 1924;198:561.

    Article  Google Scholar 

  20. Díaz JG, Ruiz JG, Herz W. Alkaloids from Delphinium Pentagynum. Phytochemistry. 2004;65:2123–7.

    Article  PubMed  Google Scholar 

  21. Shrestha PM, Katz A. Diterpenoid alkaloids from the roots of Delphinium Scabriflorum. J Nat Prod. 2004;67:1574–6.

    Article  CAS  PubMed  Google Scholar 

  22. Shrestha PM, Katz A. Norditerpenoid alkaloids from the roots of Delphinium Stapeliosum. J Nat Prod. 2000;63:2–5.

    Article  CAS  PubMed  Google Scholar 

  23. Chen L, Shan L, Gao F, Huang S, Zhou X. Alkaloids from whole plant of Delphinium Delavayi. Chin Tradit Herb Drugs. 2018;49:1773–8.

    Google Scholar 

  24. Yan LP, Chen DL, Wang FP. Structure elucidation of diterpenoid alkaloids from delphinium campylocentrum. Chin J Org Chem. 2007;27:976–80.

    CAS  Google Scholar 

  25. Zhao Q, Gou XJ, Liu W, He G, Liang L, Chen FZ, Majusine D. A new C19-diterpenoid alkaloid from Delphinium majus. Nat Prod Commun. 2015;10:2069–70.

    PubMed  Google Scholar 

  26. Suzgec S, Bitis L, Pirildar S, Ozcelik H, Zapp J, Becker H, Mericli F, Mericli AH. Diterpenoid alkaloids of Delphinium Schmalhausenii. Chem Nat Compd. 2006;42:75–7.

    Article  CAS  Google Scholar 

  27. Chen DL, Tang P, Chen QH, Wang FP. New C20-diterpenoid alkaloids from Delphinium laxicymosum var pilostachyum. Nat Prod Commun. 2014;9:623–5.

    CAS  PubMed  Google Scholar 

  28. Meriçli F, Meriçli AH, Ulubelen A, Desai HK, Pelletier SW. Norditerpenoid and diterpenoid alkaloids from Turkish Consolida orientalis. J Nat Prod. 2001;64:787–9.

    Article  PubMed  Google Scholar 

  29. Hohmann J, Forgo P, Hajdú Z, Varga E, Máthé I. Norditerpenoid alkaloids from Consolida Orietalis and complete 1H and 13 C NMR signal assignments of some lycoctonine-type alkaloids. J Nat Prod. 2002;65:1069–72.

    Article  CAS  PubMed  Google Scholar 

  30. Alva A, Grandez M, Madinaveitia A, De La Fuente G, Gavín JA. Seven new norditerpenoid alkaloids from Spanish Consolida orientalis. Helv Chim Acta. 2004;87:2110–9.

    Article  CAS  Google Scholar 

  31. Ji Ram V, Sethi A, Nath M, Pratap R. Chapter 5 - Five-Membered Heterocycles. In: Ji Ram V, Sethi A, Nath M, Pratap RBT-TC of H, editors. Elsevier; 2019. p. 149–478. Available from: https://www.sciencedirect.com/science/article/pii/B978008101033400005X.

  32. Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL. Acetylcholinesterase: From 3D structure to function. Chem Biol Interact. 2010;187:10–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Roseiro LB, Rauter AP, Serralheiro ML. M. Polyphenols as acetylcholinesterase inhibitors: structural specificity and impact on human disease. Nutr Aging. 2012;1:99–111.

  34. De Boer D, Nguyen N, Mao J, Moore J, Sorin EJ. A comprehensive review of cholinesterase modeling and simulation. Biomolecules. 2021;11(4):580.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mallender WD, Szegletes T, Rosenberry TL. Acetylthiocholine binds to Asp74 at the peripheral site of human acetylcholinesterase as the first step in the catalytic pathway. Biochemistry. 2000;39:7753–63.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was funded by Isfahan University of Medical Sciences (ID number: 3991072).

Author information

Authors and Affiliations

  1. Department of Pharmacognosy, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

    Arash Salehi, Behzad Zolfaghari, Mohammad Reza Gholami & Mustafa Ghanadian

  2. Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

    Mahmoud Aghaei

  3. Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

    Hajar Sirous

  4. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran

    Morteza Sadeghi

  5. Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

    Parham Reisi

  6. Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

    Mustafa Ghanadian

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  1. Arash Salehi
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Contributions

A.S.: Methodology, Investigation, Writing original draft. B.Z.: Supervision. M.A. AChE inhibition assay. H.S.: Docking studies, Writing manuscript. M.S.: Kinetic studies, Writing manuscript. M.R.G.: Phytochemical Investigation. P.R.: Supervision. M.G.: Methodology, Supervision, Conceptualization, Writing manuscript. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Mustafa Ghanadian.

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Salehi, A., Zolfaghari, B., Aghaei, M. et al. New amide and diterpene alkaloids with anticholinesterase activity from Delphinium cyphoplectrum roots. DARU J Pharm Sci (2024). https://doi.org/10.1007/s40199-024-00509-y

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