Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase

Bosak, Anita; Opsenica, Dejan; Šinko, Goran; Zlatar, Matija; Kovarik, Zrinka

doi:10.1016/j.cbi.2019.05.024

Cited by 27 publications

(18 citation statements)

References 48 publications

(55 reference statements)

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“…It was showed a mixed‐type inhibition. The K i (slope) and K i ′ (intercept) value of compound 2 were calculated [31] . The K i and K i ′ values were estimated as 3.3824 μM and 4.9139 μM.…”

Section: Resultsmentioning

confidence: 99%

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Design, Synthesis and Biological Evaluation of Xanthone Derivatives for Possible Treatment of Alzheimer's Disease Based on Multi‐Target Strategy

Yang

Qiao

Hui

et al. 2020

Chemistry & Biodiversity

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Four xanthone derivatives were synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs) with metal chelating ability and antioxidant ability against Alzheimer's disease (AD). Most of them exhibited potential acetylcholinesterase (AChE), butylcholinesterase (BuChE) inhibitory, antioxidant and metal chelating properties. Among them, 1-hydroxy-3-[2-(pyrrolidin-1-yl)ethoxy]-9H-xanthen-9-one had the highest ability to inhibit AChE and displayed high selectivity towards AChE (IC 50 = 2.403 � 0.002 μM for AChE and IC 50 = 31.221 � 0.002 μM for BuChE), and it was also a good antioxidant (IC 50 = 2.662 � 0.003 μM). Enzyme kinetic studies showed that this compound was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. Interestingly, its copper complex showed more significant inhibitory activity for AChE (IC 50 = 0.934 � 0.002 μM) and antioxidant activity (IC 50 = 1.064 � 0.003 μM). Molecular dockings were carried out for the four xanthone derivatives in order to further investigate the binding modes. Finally, the blood-brain barrier (BBB) penetration prediction indicated that all compounds might penetrate BBB. These results suggested that 1-hydroxy-3-[2-(pyrrolidin-1-yl)ethoxy]-9H-xanthen-9-one was promising AChEI with metal chelating ability and antioxidant ability for the further investigation.

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Section: Resultsmentioning

confidence: 99%

“…The K i (slope) and K i ' (intercept) value of compound 2 were calculated. [31] The K i and K i ' values were estimated as 3.3824 μM and 4.9139 μM. The value of α (K i /K i ') < 1 further indicated 2 was a competitive/noncompetitive mixed-type inhibitor.…”

Section: Kinetic Study Of Ache Inhibitionmentioning

confidence: 93%

Design, Synthesis and Biological Evaluation of Xanthone Derivatives for Possible Treatment of Alzheimer's Disease Based on Multi‐Target Strategy

Yang

Qiao

Hui

et al. 2020

Chemistry & Biodiversity

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“…15 . Many other compounds acting as inhibitors of cholinesterase are therefore considered as potential AD therapeutics [16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and cholinesterase inhibitory properties of new oxazole benzylamine derivatives

Šagud

Hrvat

Grgičević

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are primary targets in attenuating the symptoms of neurodegenerative diseases. Their inhibition results in elevated concentrations of the neurotransmitter acetylcholine which supports communication among nerve cells. It was previously shown for trans-4/5-arylethenyloxazole compounds to have moderate AChE and BChE inhibitory properties. A preliminary docking study showed that elongating oxazole molecules and adding a new NH group could make them more prone to bind to the active site of both enzymes. Therefore, new trans-amino-4-/5-arylethenyl-oxazoles were designed and synthesised by the Buchwald-Hartwig amination of a previously synthesised trans-chloro-arylethenyloxazole derivative. Additionally, naphthoxazole benzylamine photoproducts were obtained by efficient photochemical electrocyclization reaction. Novel compounds were tested as inhibitors of both AChE and BChE. All of the compounds exhibited binding preference for BChE over AChE, especially for trans-amino-4-/5-arylethenyl-oxazole derivatives which inhibited BChE potently (IC 50 in mM range) and AChE poorly (IC 50)100 mM). Therefore, due to the selectivity of all of the tested compounds for binding to BChE, these compounds could be applied for further development of cholinesterase selective inhibitors. HIGHLIGHTS Series of oxazole benzylamines were designed and synthesised The tested compounds showed binding selectivity for BChE Naphthoxazoles were more potent AChE inhibitors ARTICLE HISTORY

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“…Due to the composition of their active site, two enzymes can differ in selectivity and specificity for inhibitor binding [ 16 , 17 , 18 ]. Moreover, it has been well-documented that BChE reacts with a wider range of ligands than AChE and is less selective [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Benzobicyclo[3.2.1]octene Derivatives as a New Class of Cholinesterase Inhibitors

et al. 2020

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A library of amine, oxime, ether, epoxy and acyl derivatives of the benzobicyclo[3.2.1]octene were synthesized and evaluated as inhibitors of both human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The majority of the tested compounds exhibited higher selectivity for BChE. Structural adjustment for AChE seems to have been achieved by acylation, and the furan ring opening of furo-benzobicyclo[3.2.1]octadiene results for compound 51 with the highest AChE affinity (IC50 = 8.3 µM). Interestingly, its analogue, an oxime ether with a benzobicyclo[3.2.1]-skeleton, compound 32 was one of the most potent BChE inhibitors in this study (IC50 = 31 µM), but not as potent as endo-43, an ether derivative of the benzobicyclo[3.2.1]octene with an additional phenyl substituent (IC50 = 17 µM). Therefore, we identified several cholinesterase inhibitors with a potential for further development as potential drugs for the treatment of neurodegenerative diseases.

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Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase

Cited by 27 publications

References 48 publications

Design, Synthesis and Biological Evaluation of Xanthone Derivatives for Possible Treatment of Alzheimer's Disease Based on Multi‐Target Strategy

Design, Synthesis and Biological Evaluation of Xanthone Derivatives for Possible Treatment of Alzheimer's Disease Based on Multi‐Target Strategy

Design, synthesis and cholinesterase inhibitory properties of new oxazole benzylamine derivatives

Benzobicyclo[3.2.1]octene Derivatives as a New Class of Cholinesterase Inhibitors

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