Abstract
A new series of tertiary amine derivatives of chlorochalcone (4a∼4l) were designed, synthesized and evaluated for the effect on acetylcholinesterase (AChE) and buthylcholinesterase (BuChE). The results indicated that all compounds revealed moderate or potent inhibitory activity against AChE, and some possessed high selectivity for AChE over BuChE. The structure–activity investigation showed that the substituted position of chlorine significantly influenced the activity and selectivity. The alteration of tertiary amine group also leads to obvious change in bioactivity. Among them, IC50 of compound 4l against AChE was 0.17 ± 0.06 µmol/L, and the selectivity was 667.2 fold for AChE over BuChE. Molecular docking and enzyme kinetic study on compound 4l suggested that it simultaneously binds to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Further study showed that the pyrazoline derivatives synthesized from chlorochalcones had weaker activity and lower selectivity in inhibiting AChE compared to that of chlorochalcone derivatives.
Highlights
Alzheimer’s disease (AD), as one of most common diseases in the elderly population, is a chronic and progressive neurodegenerative disorder[1,2,3]
In order to explore the influence of substituent on inhibiting AChE in chalcone derivatives, halogen atoms were considered to introduce into the chalcone scaffold
Compounds 3a–3c reacted with four different alkyl amines to gain a series of amine alkyl – substituted chlorochalcone derivatives in the presence of potassium carbonate, acetone and sodium iodide
Summary
Alzheimer’s disease (AD), as one of most common diseases in the elderly population, is a chronic and progressive neurodegenerative disorder[1,2,3]. The precise etiology of AD is not elucidated enough, acetylcholinesterase (AChE) inhibitors were confirmed to be as the primary drugs to slow down the progression of AD in the present[4,5]. A lot of tertiary amine derivatives originated from natural products were synthesized and evaluated as AChE inhibitors[6,7,8,9]. The previous investigations in our laboratory suggested that chalcones with tertiary amine side chain, such as dimethylamine, diethylamine, dihydropyrrole or piperidine had more potent effects than other nitrogen-containing chalcones on inhibiting AChE10–12. Chlorine was selected to modify the chalcone derivatives, considering chlorine exist in a lot of drugs in clinic application, such as chlorphenamine, chlorpromazine, chloroquine, etc. In the investigations searching for AChE inhibitors, some chlorine-containing compounds revealed AChE inhibition properties[13,14]
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