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Design, Synthesis, and Biological Evaluation of Selective and Potent Carbazole-Based Butyrylcholinesterase Inhibitors Publisher Pubmed



Ghobadian R1 ; Nadri H2 ; Moradi A2 ; Bukhari SNA3 ; Mahdavi M4 ; Asadi M1 ; Akbarzadeh T1, 5 ; Khaleghzadehahangar H6 ; Sharifzadeh M7 ; Amini M1
Authors
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Authors Affiliations
  1. 1. Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design & Development Reseach Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 14176, Iran
  2. 2. Pharmaceutical Science Research Center and Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, 8915173143, Iran
  3. 3. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Al-jouf, Sakaka, 2014, Saudi Arabia
  4. 4. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Department of Physiology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
  7. 7. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Source: Bioorganic and Medicinal Chemistry Published:2018


Abstract

Alzheimer's disease (AD) is the most common form of dementia. Inhibition of BChE might be a useful therapeutic target for AD. A new series of Carbazole-Benzyl Pyridine derivatives were designed synthesized and evaluated as butyrylcholinesterase (BChE) inhibitors. In vitro assay revealed that all of the derivatives had selective and potent anti- BChE activities. 3-((9H-Carbazol-9-yl)methyl)-1-(4-chlorobenzyl)pyridin-1-ium chloride (compound 8f) had the most potent anti-BChE activity (IC 50 value = 0.073 μM), the highest BChE selectivity and mixed-type inhibition. Docking study revealed that 8f interacted with the peripheral site, the choline binding site, catalytic site and the acyl pocket of BChE. Physicochemical properties were accurate to Lipinski's rule. In addition, compound 8f demonstrated neuroprotective activity at 10 µM. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation at concentration of 100 µM and 10 µM respectively. The in-vivo study showed that compound 8f in 10 mg/kg increased the time spent in target quadrant in the probe day and decreased mean training period scape latency in rats. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD. © 2018 Elsevier Ltd
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