Abstract
Novel acrylamide and methacryloyl carrying piperazine-dihydrofuran derivatives (3a-p) were designed and obtained from radical cyclizations of unsaturated piperazine derivatives (1a-f) with 1,3-dicarbonyl compounds (2a-c) mediated by Mn(OAc)3. Obtained compounds were characterized by spectroscopic methods. In vitro AChE inhibitory activites of 3a-p were evaluated against AChE (Acetylcholinesterase) by Ellman method and test results showed that 3a, 3c, 3j, and 3l are the most active AChEI’s (AChE inhibitors) of our work with IC50 (half-maximal inhibitory concentration) values of 2.62, 5.29, 1.17, and 3.90 µM, respectively. Furthermore, ligand-protein interactions and inhibitory activity mechanisms of 3a and 3j were investigated by molecular docking. Finally, in silico molecular property and ADME predictions (absorption, distribution, metabolism and excretion) of potential AChEI’s were predicted by PreADMET and Molinspiration webservers. It can be concluded that the lead compound 3j show excellent inhibiton and satisfactory druglike characteristics.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder and is one of the main cause of dementia effecting elderly people
Encouraged by the results of our previous work and based on the results that were acquired by many research groups for acrylamides and piperazine compounds over recent years, in present work we studied the radicalic cyclization reaction between aromatic substituted acrylamide and methacryloyl carrying piperazine compounds (1a-f) with enolizable 1,3-dicarbonyls (dimedone (2a), acetylacetone (2b), ethylacetoacetate (2c)) via Mn(OAc
The reaction of piperazine derivative 1a with dimedone (2a) gave piperazine substituted dihydrofuran compounds 3a (10%) and 3b (45%) from the cyclization of each acyl group and these compounds were differantiated by their 1H NMR spectra
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder and is one of the main cause of dementia effecting elderly people. Based on the report of World Health Organization (WHO) about AD, about 36 million people around globe were suffering from dementia until 2010 and this would be increased to 66 million by 2030 [3]. Among them cholinergic transmission is the most commonly accepted theory and increasing levels of neurotransmitter acetylcholine in brain is crucial for the treatment of AD [7,8,9]. Acetylcholinesterase (AChE) is an enzyme in cholinesterase family which catalyzes the rapid hydrolysis of neurotransmitter acetylcholine and terminates impulse transmission at cholinergic synapses [10]. Inhibiting AChE is the most prominent way in the field of AD treatment [11] and there are many commercially available inhibitor drugs such donepezil [12], rivastigmine [13] and galantamine [14]
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