AChE inhibitory activity of N-substituted natural galanthamine derivatives

  • Bioorg Med Chem Lett. 2024 Nov 1:112:129937. doi: 10.1016/j.bmcl.2024.129937.
Mariyana Atanasova  1 ,  Georgi Stavrakov  2 ,  Irena Philipova  3 ,  Borislav Georgiev  4 ,  Jaume Bastida  5 ,  Irini Doytchinova  1 ,  Strahil Berkov  6
Affiliations
  • 1. Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria.
  • 2. Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria; Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. 9, 1113 Sofia, Bulgaria.
  • 3. Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. 9, 1113 Sofia, Bulgaria.
  • 4. Department of Plant and Fungal Diversity, Institute of Biodiversity and Ecosystem Research at the Bulgarian Academy of Sciences, 23 Acad, G. Bonchev Str., 1113 Sofia, Bulgaria.
  • 5. Departament de Biologia, Sanitat i Medi Ambient, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII 27-31, 08028 Barcelona, Spain.
  • 6. Department of Plant and Fungal Diversity, Institute of Biodiversity and Ecosystem Research at the Bulgarian Academy of Sciences, 23 Acad, G. Bonchev Str., 1113 Sofia, Bulgaria. Electronic address: [email protected].
PMID: 39218406 DOI: 10.1016/j.bmcl.2024.129937
Abstract

Galanthamine derivatives are known for their AChE inhibitory activity. Among them, galanthamine has been approved for treatment of Alzheimer's disease. N-Acetylnorgalanthamine (narcisine) and N-(2'-methyl)allylnorgalanthamine (the most potent natural AChE Inhibitor of galanthamine type) were synthetized using N-norgalanthamine as a precursor. The NMR data described previously for narcisine were revised by two-dimensional 1H-1H and 1H-13C chemical shift correlation experiments. AChE inhibitory assays showed that N-acetylnorgalanthamine and N-formylnorgalanthamine (with previously unknown activity) are 4- and 43-times, respectively, less potent than galanthamine. In vitro (AChE inhibitory) and in silico (docking, ADME) assays and comparison of N-(2'-methyl)allylnorgalanthamine with galanthamine prove that this molecule is a very promising natural AChE Inhibitor (33-times more potent than galanthamine) which further in vivo studies would provide better estimation about its applicability as a drug.

Keywords
AChE inhibitory activity; ADME; Docking; Galanthamine; Narcisine.
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