Modeling and synthesis of novel oxime derivatives as potential cholinesterase inhibitors

Ratković, Ana; Pavlović, Kristina; Barić, Danijela; Marinić, Željko; Grgičević, Ivan; Škorić, Irena

doi:10.1016/j.molstruc.2019.127149

Cited by 12 publications

(9 citation statements)

References 38 publications

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“…Further functionalization of the basic skeleton ( Scheme 2 ) was performed according to the synthesis of the formyl derivative [ 33 ], and a previously published study that combined docking and density functional theory [ 34 ]. From the formyl derivative 21 , the corresponding bicyclic oxime 22 was synthesized as a crucial substrate for further synthesis of oxime ethers 22′ .…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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“…To scrutinize the results suggested by molecular docking, we performed additional geometry optimizations of the active site docked with selected thiazoles, utilizing a quantum mechanical cluster-continuum approach [16]. We used the procedure we applied earlier to test potential AChE and BChE inhibitors [17]. For each inves-tigated system, the structure with the lowest estimated free energy and K i was chosen and prepared for QM optimization.…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

The structure–activity relationship and computational studies of 1,3-thiazole derivatives as cholinesterase inhibitors with anti-inflammatory activity

Modrić¹,

Božičević²,

Odak³

et al. 2022

Comptes Rendus. Chimie

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In our previous research, some screened 1,3-thiazole fragments were found to be potent by inhibiting LPS-induced TNFα and IL-8 release with IC 50 values in the µM range without cytotoxic activity. In the current study, 1,3-thiazole fragments were further investigated as potent cholinesterase inhibitors prompted by the previously documented anti-inflammatory effect of AChE inhibitors. Molecular docking enabled insight into stabilizing interactions between the selected thiazoles and the active site of AChE and BChE. According to these experimental results, the cholinesterase inhibitory and anti-inflammatory activity of 1,3-thiazoles were correlated and confirmed that the same compounds inhibited LPS-stimulated TNFα cytokine production in PBMCs and enzymes cholinesterases.

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“…Third, vertebrates have also another cholinesterase enzyme, butyrylcholinesterase (BuChE) that protects AChE from neuroactive peptides and other toxic anti-cholinesterase agents, beyond its ability to hydrolyze acetylcholine. [20,21] It is reported that in advanced stages of Alzheimer's, the activity of AChE may decrease up to 50 %, with a simultaneous significant enhancement of BuChE activity giving relevance to the anti-cholinesterase agent's selectivity. [20,22,23] Within this scientific framework, 1-methylpyridin-1-ium-2carboxylate (known as homarine) was selected as a suitable chemical structure to design new AChE inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Homarine Alkyl Ester Derivatives as Promising Acetylcholinesterase Inhibitors

et al. 2021

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Reversible acetylcholinesterase (AChE) inhibitors are key therapeutic tools to modulate the cholinergic connectivity compromised in several degenerative pathologies. In this work, four alkyl esters of homarine were synthesized and screened by using Electrophorus electricus AChE and rat brain AChE-rich fraction. Results showed that all homarine alkyl esters are able to inhibit AChE by a competitive inhibition mode. The effectiveness of AChE inhibition increases with the alkyl side chain length of the homarine esters, being HOÀ C 16 (IC 50 = 7.57 � 3.32 μM and K i = 18.96 � 2.28 μM) the most potent inhibitor. The fluorescence quenching studies confirmed that HOÀ C 16 is the compound with higher selectivity and affinity for the tryptophan residues in the catalytic active site of AChE. Preliminary cell viability studies showed that homarine esters display no toxicity for human neuronal SH-SY5Y cells. Thus, the long-chain homarine esters emerge as new anti-cholinesterase agents, with potential to be considered for therapeutic applications development.

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Modeling and synthesis of novel oxime derivatives as potential cholinesterase inhibitors

Cited by 12 publications

References 38 publications

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

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

The structure–activity relationship and computational studies of 1,3-thiazole derivatives as cholinesterase inhibitors with anti-inflammatory activity

Homarine Alkyl Ester Derivatives as Promising Acetylcholinesterase Inhibitors

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