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Design, Synthesis, in Vivo and in Vitro Studies of 1,2,3,4-Tetrahydro-9H-Carbazole Derivatives, Highly Selective and Potent Butyrylcholinesterase Inhibitors Publisher Pubmed



Ghobadian R1 ; Esfandyari R1 ; Nadri H2 ; Moradi A2 ; Mahdavi M3 ; Akbarzadeh T1, 4 ; Khaleghzadehahangar H5 ; Edraki N6 ; Sharifzadeh M7 ; Amini M1
Authors

Source: Molecular Diversity Published:2020


Abstract

Abstract: Inhibition of butyrylcholinesterase (BChE) might be a useful therapeutic target for Alzheimer’s disease (AD). A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit (> 100 µM), they were selective potent BChE inhibitors. 1-(2-(6-fluoro-1,2,3,4-tetrahydro-9H-carbazole-9-yl)ethyl)piperidin-1-ium chloride (15 g) had the most potent anti-BChE activity (IC50 value = 0.11 μM), the highest BChE selectivity and mixed-type inhibition. Pharmacokinetic properties were accordant to Lipinski rule and compound 15g demonstrated neuroprotective and inhibition of β-secretase (BACE1) activities. Furthermore, in vivo study of compound 15g in Morris water maze task has confirmed memory improvement in scopolamine-induced impairment. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD. Graphical abstract: A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit, they were selective potent BChE inhibitors. Compound 15g had the most potent anti-BChE activity. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.[Figure not available: see fulltext.] © 2019, Springer Nature Switzerland AG.
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