Molecular approach to promising cholinesterase inhibitory effect of several amaryllidaceae alkaloids: Further re-investigation


Orhan İ., ŞENOL DENİZ F. S. , EREN G., Sener B.

South African Journal of Botany, vol.136, pp.175-181, 2021 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 136
  • Publication Date: 2021
  • Doi Number: 10.1016/j.sajb.2020.03.017
  • Journal Name: South African Journal of Botany
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, CAB Abstracts, Veterinary Science Database
  • Page Numbers: pp.175-181
  • Keywords: Alkaloid, Cholinesterase inhibition, Tetrahydroisoquinoline, N-norgalanthamine, ACETYLCHOLINESTERASE INHIBITION, ISOQUINOLINE ALKALOIDS, BIOLOGICAL-ACTIVITIES, NATURAL-PRODUCTS, LYCORINE SERIES, BUTYRYLCHOLINESTERASE, GALANTHAMINE, DERIVATIVES, DOCKING
  • Gazi University Affiliated: Yes

Abstract

© 2020 SAABAll cholinesterase (ChE) inhibitory drugs in clinical use are nitrogenous compounds and among them, galanthamine as the latest anticholinesterase drug, contains a tetrahydroisoquinoline structure. For this reason, isoquinoline alkaloids seem to be attractive in search for novel drug candidates towards Alzheimer's disease (AD). Therefore, in the current work, we investigated inhibitory capacity of several alkaloids representing expanding group of biogenetically-related isoquinoline alkaloids from the Amaryllidaceae including lycorine, (+)-9-O-demethylhomolycorine, 6-hydroxybuphanisine, 9-O-demethoxymontanine, 3-epi-hydroxy-bulbispermine, tazettine, haemanthamine, (+)-haemanthidine, (-)-crinine, 8-hydroxy-9-methoxycrinine, and N-norgalanthamine against ChEs by microtiter enzyme inhibition assays. Our findings indicated that N-norgalanthamine is the most active one inhibiting both acetylcholinesterase (AChE, IC50 = 2.42 ± 0.16 µg/mL) and butyrylcholinesterase (BChE, IC50 = 20.87 ± 1.01 µg/mL) at 100 μg/mL, whereas IC50 values of galanthamine used as the reference were 1.33 ± 0.11 µg/mL and 37.69 ± 2.93 µg/mL for AChE and BChE, respectively. Beside this, 8-hydroxy-9-methoxycrinine was a strong inhibitor of AChE (IC50 = 6.92 ± 0.51 µg/mL), while (+)-9-O-demethylhomolycorine displayed a moderate BChE inhibition (IC50 = 83.57 ± 1.36 µg/mL). Relevantly, 8-hydroxy-9-methoxycrinine and N-norgalanthamine were docked into active gorges of hAChE (PDB: 4EY6) and hBChE (PDB: 4TPK), which pointed out the detail that N-norgalanthamine displayed a very similar binding mode of to that of galanthamine. Moreover, both AChE-inhibiting alkaloids were found to stably bind to hAChE active site occupying the middle of the gorge between the catalytic site and the peripheral anionic site. 8-Hydroxy-9-methoxycrinine was also docked into the active site of BChE. We can conclude that among the tested alkaloids, N-norgalanthamine with dual ChE inhibitory effect seems to be the most promising anti-Alzheimer candidate molecule for future experiments.