Novel tetrahydrocarbazole benzyl pyridine hybrids as potent and selective butryl cholinesterase inhibitors with neuroprotective and β-secretase inhibition activities

Roshanak Ghobadian, Mohammad Mahdavi, Hamid Nadri, Alireza Moradi, Najmeh Edraki, Tahmineh Akbarzadeh, Mohammad Sharifzadeh, Bukhari Syed Nasir Abbas, Mohsen Amini

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Butyrylcholinesterase (BuChE) inhibitors have become interesting target for treatment of Alzheimer's disease (AD). A series of dual binding site BuChE inhibitors were designed and synthesized based on 2,3,4,9-tetrahydro-1H-carbazole attached benzyl pyridine moieties. In-vitro assay revealed that all of the designed compounds were selective and potent BuChE inhibitors. The most potent BuChE inhibitor was compound 6i (IC50 = 0.088 ± 0.0009 μM) with the mixed-type inhibition. Docking study revealed that 6i is a dual binding site BuChE inhibitor. Also, Pharmacokinetic properties for 6i were accurate to Lipinski's rule. In addition, compound 6i demonstrated neuroprotective and β-secretase (BACE1) inhibition activities. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation at concentration of 100 μM and 10 μM respectively. Generally, the results are presented as new potent selective BuChE inhibitors with a therapeutic potential for the treatment of AD.

Original languageEnglish
Pages (from-to)49-60
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume155
DOIs
Publication statusPublished - 15 Jul 2018
Externally publishedYes

Fingerprint

Butyrylcholinesterase
Amyloid Precursor Protein Secretases
Cholinesterase Inhibitors
Alzheimer Disease
Binding Sites
Pharmacokinetics
Inhibitory Concentration 50
Inhibition (Psychology)
pyridine
Assays
Therapeutics
Agglomeration
Peptides

Keywords

  • 2,3,4,9-Tetrahydro-1H-carbazole
  • Alzheimer's disease
  • Butyrylcholinesterase
  • Docking study
  • In-vitro assay

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Novel tetrahydrocarbazole benzyl pyridine hybrids as potent and selective butryl cholinesterase inhibitors with neuroprotective and β-secretase inhibition activities. / Ghobadian, Roshanak; Mahdavi, Mohammad; Nadri, Hamid; Moradi, Alireza; Edraki, Najmeh; Akbarzadeh, Tahmineh; Sharifzadeh, Mohammad; Syed Nasir Abbas, Bukhari; Amini, Mohsen.

In: European Journal of Medicinal Chemistry, Vol. 155, 15.07.2018, p. 49-60.

Research output: Contribution to journalArticle

Ghobadian, Roshanak ; Mahdavi, Mohammad ; Nadri, Hamid ; Moradi, Alireza ; Edraki, Najmeh ; Akbarzadeh, Tahmineh ; Sharifzadeh, Mohammad ; Syed Nasir Abbas, Bukhari ; Amini, Mohsen. / Novel tetrahydrocarbazole benzyl pyridine hybrids as potent and selective butryl cholinesterase inhibitors with neuroprotective and β-secretase inhibition activities. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 155. pp. 49-60.
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