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Novel Tetrahydrocarbazole Benzyl Pyridine Hybrids As Potent and Selective Butryl Cholinesterase Inhibitors With Neuroprotective and Β-Secretase Inhibition Activities Publisher Pubmed



Ghobadian R1 ; Mahdavi M2 ; Nadri H3 ; Moradi A3 ; Edraki N4 ; Akbarzadeh T1, 5 ; Sharifzadeh M6 ; Bukhari SNA7 ; Amini M1
Authors
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Authors Affiliations
  1. 1. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 14176, Iran
  2. 2. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Pharmaceutical Science Research Center and Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, 8915173143, Iran
  4. 4. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  5. 5. Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  7. 7. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Al-jouf, Sakaka, 2014, Saudi Arabia

Source: European Journal of Medicinal Chemistry Published:2018


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. © 2018 Elsevier Masson SAS
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