Synthesis, characterization, acetylcholinesterase inhibition, and molecular docking studies of new piperazine substitute
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Medicinal Chemistry Research https://doi.org/10.1007/s00044-020-02599-0
ORIGINAL RESEARCH
Synthesis, characterization, acetylcholinesterase inhibition, and molecular docking studies of new piperazine substituted dihydrofuran compounds Sait Sari1 Mehmet Yilmaz ●
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Received: 10 April 2020 / Accepted: 29 June 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Novel unsaturated piperazine and homopiperazine derivatives (3a–h) were synthesized in medium to good yields by acylation reactions of piperazine and homopiperazine with methacrylic anhydride (2a) and benzoyl chloride (2b). Piperazine containing dihydrofuran compounds (5a–l) were obtained from radical addition and cyclizations of 3a–h with 1,3dicarbonyl compounds such as dimedone (4a), ethyl acetoacetate (4b) and acetylacetone (4c) mediated by Mn(OAc)3 for the first time. While the reaction of 3b (1-methacryloylpiperazine) with 4a and 4b gave bis-dihydrofurans (5b and 5d) beside mono-dihydrofurans (5a and 5c), the reaction of 3b–e, 3g, 3h, and 3e with 1,3-dicarbonyl compounds gave mono dihydrofuran compounds (5f–l) in medium to high yields. Structures of all novel compounds were determined by melting point analysis, 1H NMR, 13C NMR, HRMS, and FTIR methods. All piperazine containing dihydrofuran compounds were evaluated for their inhibitory activities toward acetylcholinesterase (AChE) by Ellman method and IC50 values were presented. Compounds 5c, 5d, 5e, 5i, and 5l show highest inhibitory activities with IC50 values of 5.79, 3.89, 5.07, 4.30, and 2.24 µM, respectively. In addition, molecular docking studies were performed on selected structures 5d, 5i, and 5l to investigate ligand–protein interactions. Binding energies were calculated and compared with standart drug donepezil. Keywords Piperazine Dihydrofuran Radical cyclization Acetylcholinesterase inhibition ●
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Introduction Alzheimer’s disease (AD) is a progressive and chronic neurodegenerative disorder which is one of the main causes of dementia that effects elder people (Anand et al. 2014; Gao et al. 2018). Among the various proposed pathogenesis hyphotesis of AD, cholinergic hyphothesis is the most commonly accepted and the decrease of neurotransmitter acetylcholine levels in the brain is considered the most prominent cause of AD (Akasofu et al. 2008; Dumas and Newhouse 2011; Molinuevo and Gauthier 2013). Acetylcholinesterase (AChE) is an enzyme belongs to cholinesterase family and the main biological function of AChE is to terminate impulse transmission at cholinergic
* Mehmet Yilmaz [email protected] 1
Department of Chemistry, Faculty of Arts and Sciences, Kocaeli University, Umuttepe, 41380 Kocaeli, Turkey
synapses by catalyzing the rapid hydrolysis of the neurotransmitter acetylcholine (Tougu 2001; Berwaldt et al. 2019). Inhibiting AChE is the most effective and promising way and AChE inhibitors such as donepezil (Sugimoto et al. 1995), rivastigmine (Weintraub et al. 2011) and galantamine (Giacobini 2004) are freque
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