New hybrids of tacrine and indomethacin as multifunctional acetylcholinesterase inhibitors

Kamil Zawada,František Trejtnar,Kamila Czarnecka,Paweł Szymański,Przemysław Wójtowicz,Paweł Kręcisz,Jana Mandíková,Mariusz Staśkiewicz,Robert Skibiński,Jakub Jończyk,Katarzyna Dziubek,Marek Bajda,Małgorzata Girek

doi:10.1007/s11696-020-01295-y

Abstract

A new series of hybrid compounds were designed, consisting of anti-AChE and BuChE activity components with an anti-inflammatory component. A series of 9-amino-1,2,3,4-tetrahydroacridine and indomethacin derivatives were synthesized. All compounds were created using alkyldiamine with different chain lengths as a linker. Various biological activities were evaluated, including inhibitory activity against AChE and BuChE. The tested compounds showed high inhibitory activities against cholinesterases. The IC50 values for all compounds ranging from 10 nM to 7 µM. The potency of inhibition was much higher than well-known AChE and BuChE inhibitors (tacrine and donepezil). Compound 3h had the strongest inhibitory activity; kinetic studies showed it to have a mixed-type of acetylcholinesterase inhibition properties. The cytotoxicity of the newly-synthesized compounds against HepG2 (hepatocarcinoma cells) and EA.hy96 (human vein endothelial cells) cell lines was determined using the MTT and MTS tests. All investigated compounds presented similar cytotoxic activity against HepG2 and EA.hy926 cell line, ranged in micromolar values. Compounds with longer linkers showed higher antioxidant activity. The most active compound was 3h. Docking studies confirmed interactions with important regions of AChE and BuChE. Its multifunctional properties, i.e. high activity against AChE and BuChE, antioxidant activity and low cytotoxicity, highlight 3h as a promising agent for the treatment of AD.

Highlights

The most common human neurodegenerative disease is Alzheimer’s disease (AD)—which was described for the first time by Alois Alzheimer over 100 years ago
Previous studies of AD pathophysiology have examined the formation of β-amyloid deposits, prolonged oxidative stress, cholinergic system dysfunctions (Tayeb et al 2012; Zimmer et al 2014; Blass 2002), inflammations, aging, heart disease, hypertension, hypercholesterolemia, diabetes, gene mutations associated with the incorrect tau protein (Cataldo et al 2010), as well as the imbalance of bio-metals (Tayeb et al 2012; Huang et al 2014)
The new acetylcholinesterase inhibitors were created by connecting diamine derivatives of tetrahydroacridine with indomethacin

Summary

Introduction

The most common human neurodegenerative disease is Alzheimer’s disease (AD)—which was described for the first time by Alois Alzheimer over 100 years ago. AD causes a significant decrease in cognitive abilities in people over 60 years old (Obulesu and Jhansilakshmi 2014). The incidence of AD increases with age: rising from 5% among people aged 65–50% over the age 85 (Townsend and Praticò 2005). The disease has a progressive and multifunctional character. Its development involves a lot of factors but a complete etiology has not been discovered (Tayeb et al 2012) and no method exists which can be used to treat AD (Côté et al 2012). Existing drugs only slow the progression of the disease and slightly improve patient comfort and everyday life. Previous studies of AD pathophysiology have examined the formation of β-amyloid deposits, prolonged oxidative stress, cholinergic system dysfunctions (Tayeb et al 2012; Zimmer et al 2014; Blass 2002), inflammations, aging, heart disease, hypertension, hypercholesterolemia, diabetes, gene mutations associated with the incorrect tau protein (Cataldo et al 2010), as well as the imbalance of bio-metals (Tayeb et al 2012; Huang et al 2014)

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