Design, synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors

Liu, Haoran; Liu, Xianjun; Fan, Haoqun; Tang, Jingjing; Gao, Xiaohui; Liu, Wu-Kun

doi:10.1016/j.bmc.2014.08.033

Cited by 56 publications

(32 citation statements)

References 30 publications

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“…Flavokawain B, first isolated from Piper methysticum Forst [11] is another natural product containing the chalcone scaffold. In our laboratory, we found that flavokawain B Mannich base derivatives had AChE inhibitory effects [12] and, following this discovery, we synthesized a series of tertiary amine chalcone derivatives, some of which had quite potent AChE inhibitory activity(IC 50 =0.21~4.68 μmol/L) [13–16]. In our studies, we investigated AChE inhibitory effects of various tertiary amine groups, the nature of the spacer between the chalcone scaffold and the tertiary amine side-chain, as well as the effects of other substituents in the chalcone scaffold, but no investigations into the influence of different substituent positions of tertiary amine groups were reported.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationship investigation of coumarin–chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors

et al. 2018

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Chalcones containing tertiary amine side-chains have potent activity as acetylcholinesterase (AChE) inhibitors. However, the effects of the location of the tertiary amine groups as well as of other groups on AChE and butyrylcholinesterase (BChE) activity have not been reported. Here, we report the synthesis and testing of 36 new coumarin-chalcone hybrids (5d-7j, 9d-11f, 12k-13m) against AChE and BChE. The nature and position of the chalcone substituents had major effects on inhibitory activity as well as selectivity for AChE over BChE. Compounds with para-substituted chalcone fragments in which the substituents were choline-like had potent activity against AChE and poor activity against BChE, while ortho-substituted analogs exhibited an opposite effect. Replacement of the terminal amine groups by amide, alkyl or alkenyl groups abrogated activity. Compound 5e showed potent inhibitory activity [Formula: see text]) and good selectivity for AChE over BChE (ratio 27.4), and a kinetic study showed that 5e exhibited mixed-type inhibition against AChE. Computational docking results indicate that 5e binds to Trp 279, Tyr334 and Trp 84 in AChE, but only to Trp 82 in BChE. Overall, the results show that coumarin-chalcone hybrids with choline-like side-chains have promising activity and selectivity against AChE and be promising therapeutic leads for Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

Structure–activity relationship investigation of coumarin–chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors

et al. 2018

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“…As flavokawain B is a naturally occurring chalcone isolated from the root of Piper methysticum (Jeong et al, ), a series of chalcone with tertiary amine side chains were synthesized, which were confirmed possessing inhibitory effect on AChE in subsequent experiments. Some of them have better selectivity in inhibiting AChE over butyrylcholinesterase (BChE) in our reports (Liu et al, b; Liu et al, ). Most recently, we have discovered cinnamic acid derivatives similar to chalcone scaffold can inhibit AChE.…”

Section: Introductionmentioning

confidence: 58%

Structure–activity study of fluorine or chlorine‐substituted cinnamic acid derivatives with tertiary amine side chain in acetylcholinesterase and butyrylcholinesterase inhibition

Gao

Tang

Liu

et al. 2019

Drug Development Research

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In this study, a series of new fluorine or chlorine-substituted cinnamic acid derivatives that contain tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results show that almost all the derivatives containing tertiary amine side chain (compounds 4a-9d) exhibit moderate or potent activity in AChE inhibition. By contrast, their parent compounds (compounds 3a-3f) in the absence of tertiary amine moitery exhibit poor inhibitory activity against AChE. For the compounds containing pyrroline or piperidine side chain, the bioactivity in AChE inhibition is much intense than those containing N,N-diethylamino side chain. The chlorine or fluorine substituted position produces a significant effect on the bioactivity and selectivity in AChE inhibition. Most of the compounds that contain para-substituted fluorine or chlorine exhibit potent activity against AChE and poor activity against BChE, while ortho-substituted analogs show the opposite effect. It is worth noticing that the compounds containing N,N-diethylamino side chain are exceptions to this pattern. Among the newly synthesized compounds, compounds 6d are the most potent in AChE inhibition (IC 50 = 1.11 ± 0.08 μmol/L) with high selectivity for AChE over BChE (selectivity ratio: 46.58). An enzyme kinetic study of compounds 6d suggests it produces a mixed-type inhibitory effect in AChE. K E Y W O R D Scholinesterase inhibitors, cinnamic acid, halogen

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“…These activities have been related to their flexible structure, which probably allows effective binding to enzymes and receptors. However, few investigations have been reported on their inhibiting potential towards AChE and BuChE . The epoxidation of chalcones, which furnishes useful building blocks in organic and pharmaceutical chemistry, has also not been extensively investigated for its biological activities.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the inhibitory potential towards carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase of chalcone and chalcone epoxide

Stellenboom

2018

J Biochem & Molecular Tox

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Chalcones and chalcone epoxides are important synthetic intermediates in organic and medicinal chemistry. Chalcones possess a broad spectrum of biological activities; however, 1,3-diphenyl-2-propenone or chalcone has not been given the attention it deserve as its substituted derivatives. In this study, the inhibition effects of chalcone and its epoxidated derivative chalcone epoxide against human carbonic anhydrase isozymes I and II (hCA I and hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were evaluated. The results obtained showed that both compounds exhibited potent inhibitory activity, with IC 50 values less than 10 µM. IC 50 values in the submicromolar (hCA I and hCA II) to low micromolar range (AChE and BuChE) were observed for both compounds.

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Design, synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors

Cited by 56 publications

References 30 publications

Structure–activity relationship investigation of coumarin–chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors

Structure–activity relationship investigation of coumarin–chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors

Structure–activity study of fluorine or chlorine‐substituted cinnamic acid derivatives with tertiary amine side chain in acetylcholinesterase and butyrylcholinesterase inhibition

Comparison of the inhibitory potential towards carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase of chalcone and chalcone epoxide

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