ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

New hybrids of tacrine and indomethacin as multifunctional acetylcholinesterase inhibitors

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

Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Faculty of Pharmacy, Medical University of Lodz, Lodz, Poland

E-mail: pawel.szymanski@umed.lodz.pl

Received: 14 January 2020  Accepted: 22 July 2020

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.

Keywords: Acetylcholinesterase inhibitors; Alzheimer’s disease; Indomethacin; Multifunctional drugs

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-020-01295-y

Chemical Papers 75 (1) 249–264 (2021)