Pharmacological Evaluation and Docking Studies of 3-Thiadiazolyl- and Thioxo-1,2,4-triazolylcoumarin Derivatives as Cholinesterase Inhibitors

Ahsan Raza,Aliya Ibrar,Jamshed Iqbal,Muhammad Muddassar,Aftab Ahmed Khan,Aamer Saeed

doi:10.5402/2012/707932

Abstract

Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is considered a promising strategy for the treatment of Alzheimer's disease (AD). This research project aims to provide a comprehensive knowledge of newly synthesized coumarin analogues with anti-AD potential. In the present work a series of 3-thiadiazolyl- and thioxo-1,2,4-triazolylcoumarins derivatives were designed, synthesized, and tested as potent inhibitors of cholinesterases. These compounds were assayed against AChE from electrophorus electricus and rabbit; and BChE from horse serum and rabbit by Ellman's method using neostigmine methylsulphate and donepezil as reference drugs. Some of the assayed compounds proved to be potent inhibitors of AChE and BChE with Ki values in the micromolar range. 4b was found to be the most active compound with Ki value 0.028 ± 0.002 μM and higher selectivity for AChE/BChE. The ability of 4b to interact with AChE was further confirmed through computational studies, in which a primary binding was proved to occur at the active gorge site, and a secondary binding was revealed at the peripheral anionic site. Structure activity relationships of prepared compounds were also discussed.

Highlights

Alzheimer’s disease (AD), Parkinson’s disease, and agerelated memory disorders always remain in keen interest of researchers
The present paper focuses on synthesis of new class of coumarins which could prove as potent therapeutic moieties against progression of AD in future
The cholinesterase inhibition studies revealed that all compounds were potential inhibitors of the investigated enzymes and can be used for treatment of Alzheimer’s disease

Summary

Introduction

Alzheimer’s disease (AD), Parkinson’s disease, and agerelated memory disorders always remain in keen interest of researchers. AD is a progressive neurodegenerative disorder that is characterized by the appearance of neurofibrillary tangles, neuritic plagues within the brain of AD patients, [1] rapid loss of synapses, and degeneration of basal cholinergic neurons [2]. Loss of cholinergic neurons causes reduction in cortical and hippocampal levels of the neurotransmitter acetylcholine (ACh) that leads to impairment in cognitive functions as well [3,4,5]. Various anti-AChE agents, that is, ensaculine, donepezil, propidium, rivastigmine, and tacrine (Figure 1) have shown slight improvement in cognitive and memory disorders [10]. These available nitrogen containing anti-AChE drugs have certain side effects and lesser CNS permeability. New drugs are required for the treatment of AD with better CNS penetration and decreased toxic effects

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