Analogues of 2′-hydroxychalcone with modified C4-substituents as the inhibitors against human acetylcholinesterase
Sri Devi SukumaranShah Bakhtiar NasirJia Ti TeeMichael J. C. BuckleRozana OthmanNoorsaadah Abd RahmanVannajan Sanghiran LeeSyed Nasir Abbas BukhariChin Fei Chee
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Abstract:
A series of C4-substituted tertiary nitrogen-bearing 2'-hydroxychalcones were designed and synthesised based on a previous mixed type acetylcholinesterase inhibitor. Majority of the 2'-hydroxychalcone analogues displayed a better inhibition against acetylcholinesterase (AChE) than butyrylcholinesterase (BuChE). Among them, compound 4c was identified as the most potent AChE inhibitor (IC50: 3.3 µM) and showed the highest selectivity for AChE over BuChE (ratio >30:1). Molecular docking studies suggested that compound 4c interacts with both the peripheral anionic site (PAS) and catalytic anionic site (CAS) regions of AChE. ADMET analysis confirmed the therapeutic potential of compound 4c based on its blood-brain barrier penetrating. Overall, the results suggest that this 2'-hydroxychalcone deserves further investigation into the therapeutic lead for Alzheimer's disease (AD).Keywords:
Butyrylcholinesterase
IC50
Acetylcholinesterase inhibitor
Cholinesterase
Docking (animal)
Antlion is used in traditional medicine by natives of the southern part of Nigeria particularly the Yorubas for memory enhancement. The progress made so far in the use of this organism as a memory booster lead to investigating the acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) (the key enzymes in the pathogenesis of Alzheimer's disease) inhibitory activities of methanolic and phosphate buffered saline (PBS) extracts. The activities of these enzymes were investigated using Ellman’s method. The kinetics of the inhibition patterns was also studied using eserine as the standard inhibitor. The concentration of the extract required for 50% inhibition (IC50) of the AChE was 49.00 ± 1.20 and 271.40 ± 0.10 µg/mL, for the PBS and methanolic extracts respectively, compared to Eserine with IC50 of 2.25 x 10-2 ± 0.15 x 10-2 µg/mL. Similarly, the IC50 for the BuChE was 66.30 ± 0.40 and 216.70 ± 1.10 µg/mL respectively, for the methanol and PBS extracts, compared to Eserine with IC50 of 1.10 ± 0.30 µg/mL. The pattern of inhibition of the BuChE in the presence of the extracts was non-competitive, while AChE exhibited non-competitive and competitive inhibitions for the methanolic and PBS extracts respectively. It is therefore evident that extracts of the antlion larvae contained cholinesterase inhibitors which might be binding to AChE and BuChE; with the PBS extract inhibitory activity towards AChE being more potent than the methanolic extract. Suggesting a beneficial effect in cognitive deficit and related dementia associated with Alzheimer’s disease.
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IC50
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Cholinesterase inhibitors have been widely used for the treatment of patients with dementia. Monitoring of the cholinesterase activity in the blood is used as an indicator of the effect of the cholinesterase inhibitors in the brain. The selective measurement of cholinesterase with low tissue dilution is preferred for accurate monitoring; however, the methods have not been established. Here, we investigated the effect of tissue dilution on the action of cholinesterase inhibitors using a novel radiometric method with selective substrates, N-[(14)C]methylpiperidin-4-yl acetate ([(14)C]MP4A) and (R)-N- [(14)C]methylpiperidin-3-yl butyrate ([(14)C]MP3B_R), for AChE and butyrylcholinesterase (BChE) respectively.We investigated the kinetics of hydrolysis of [(14)C]-MP4A and [(14)C]-MP3B_R by cholinesterases, and evaluated the selectivity of [(14)C]MP4A and [(14)C]MP3B_R for human AChE and BChE, respectively, compared with traditional substrates. Then, IC(50) values of cholinesterase inhibitors in minimally diluted and highly diluted tissues were measured with [(14)C]MP4A and [(14)C]MP3B_R.AChE and BChE activities were selectively measured as the first-order hydrolysis rates of [(14)C]-MP4A and [(14)C]MP3B_R respectively. The AChE selectivity of [(14)C]MP4A was an order of magnitude higher than traditional substrates used for the AChE assay. The IC(50) values of specific AChE and BChE inhibitors, donepezil and ethopropazine, in 1.2-fold diluted human whole blood were much higher than those in 120-fold diluted blood. In addition, the IC(50) values of donepezil in monkey brain were dramatically decreased as the tissue was diluted.This method would effectively monitor the activity of cholinesterase inhibitors used for therapeutics, pesticides and chemical warfare agents.
Butyrylcholinesterase
Cholinesterase
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Butyrylcholinesterase
Cholinesterase
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A series of C4-substituted tertiary nitrogen-bearing 2'-hydroxychalcones were designed and synthesised based on a previous mixed type acetylcholinesterase inhibitor. Majority of the 2'-hydroxychalcone analogues displayed a better inhibition against acetylcholinesterase (AChE) than butyrylcholinesterase (BuChE). Among them, compound 4c was identified as the most potent AChE inhibitor (IC50: 3.3 µM) and showed the highest selectivity for AChE over BuChE (ratio >30:1). Molecular docking studies suggested that compound 4c interacts with both the peripheral anionic site (PAS) and catalytic anionic site (CAS) regions of AChE. ADMET analysis confirmed the therapeutic potential of compound 4c based on its blood-brain barrier penetrating. Overall, the results suggest that this 2'-hydroxychalcone deserves further investigation into the therapeutic lead for Alzheimer's disease (AD).
Butyrylcholinesterase
IC50
Acetylcholinesterase inhibitor
Cholinesterase
Docking (animal)
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Citations (9)
Butyrylcholinesterase
Cholinesterase
Cite
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Butyrylcholinesterase
Cholinesterase
Huperzine A
Carbamate
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Cholinesterase plays a vital role in the decline of cholinergic transmission and thus can contribute to the development of Alzheimer’s disease (AD). Thus, compounds that can inhibit acetylcholinesterase (AChe) and butyrylcholinesterase (BuChe) are the potential drugs for the treatment of AD. A series of novel pyrrolopyrimidine derivatives was synthesized and evaluated for their inhibitory activity against cholinesterase by Ellman method. Among the ten newly synthesized compounds, 4-(4-((4-(difluoromethoxy)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzoate was the most potent molecule identified with the IC50 values of 18 µM and 17 µM on AChe and BuChe respectively. Keywords: Acetylcholinesterase, alzheimer’s disease, butyrylcholinesterase, cholinergic transmission, inhibition, pyrrolopyrimidine.
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