Butyrylcholinesterase inhibitors as potential anti-Alzheimer’s agents: an updated patent review (2018-present)

Fernandez‐Bolanos, J.; López, Óscar

doi:10.1080/13543776.2022.2083956

Cited by 17 publications

(12 citation statements)

References 71 publications

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“…The IC 50 values thus obtained are 33 µM and 2.5 µM for AChE and BChE, respectively. This can be compared to the IC 50 values of the reference inhibitors: Rivastigmine was was reported to have an IC 50 value in AChE of 71µM [42] or 501 µM [43], whereas for Tacrine the values range between 0.2-0.45 µM [44,45]. Ondansetron is hence a more potent binder to AChE than Rivastigmine, but less so than Tacrine, which agrees perfectly with the MMGBSA data of Table 2.…”

Section: A Of Ondansetron In the Enzymessupporting

confidence: 74%

In silico and in vitro Studies Confirm Ondansetron as a Novel Acetylcholinesterase and Butyrylcholinesterase Inhibitor

Gholami

Minai-Tehrani

Eriksson

2022

Preprint

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is growing rapidly among the elderly population around the world. Studies show that a lack of acetylcholine and butyrylcholine due to the overexpression of enzymes Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) may lead to reduced communication between neuron cells. As a result, seeking novel inhibitors targeting these enzymes might be vital for future treatment of AD. Ondansetron is used to prevent nausea and vomiting caused by chemotherapy or radiation treatments, and is herein shown to be a potent inhibitor of cholinesterase. Comparison is made between Ondansetron and FDA-approved cholinesterase inhibitors Rivastigmine and Tacrine. Molecular docking demonstrates that interactions between the studied ligand and aromatic residues in the peripheral region of the active site are important in binding. Molecular dynamics simulations and binding pose metadynamics show that Ondansetron is highly potent against both enzymes, and far better than Rivastigmine. Inhibitor activities evaluated by in vitro studies confirm that the drug inhibits AChE and BChE by non-competitive and mixed inhibition, respectively, with IC50 values 33 µM (AChE) and 2.5 µM (BChE). Based on the findings, we propose that Ondansetron may have therapeutic applications in inhibiting cholinesterase, especially for BChE.

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Section: A Of Ondansetron In the Enzymessupporting

confidence: 74%

In silico and in vitro Studies Confirm Ondansetron as a Novel Acetylcholinesterase and Butyrylcholinesterase Inhibitor

Gholami

Minai-Tehrani

Eriksson

2022

Preprint

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“…BChE is a closely related enzyme known as a pseudo cholinesterase, catalyzes the breakdown of different choline esters. The inhibition of BChE is also useful as it bears 65% of structural resemblance with AChE [23].…”

Section: Kinetic Studiesmentioning

confidence: 99%

“…Anti-ChE activity of the isolated compounds from the aril of M. fragrans a a Data are expressed as mean ± SD (three independent experiments) ] revealed similar trend in the ChEI activity of the fractions, however, the ethyl acetate fraction of the aril (IC 50 = 68.16 µg/mL) demonstrated higher anti-BChE activity than that of seeds (IC 50 = 145.84 μg/mL). The selective inhibition of the BChE can be achieved by the bulky inhibitors due to the slight difference in the structure of the deep gorge with that of AChE[23]. In this respect, the selective inhibition of BChE by different fractions of the plant can be explained.…”

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confidence: 99%

Phytochemical analysis and anticholinesterase activity of aril of Myristica fragrans Houtt

Rastegari

Manayi²,

Rezakazemi³

et al. 2022

BMC Chemistry

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In this study, the ethyl acetate fraction of Myristica fragrans Houtt. was investigated for its in vitro anticholinesterase activity as well as neuroprotectivity against H2O2-induced cell death in PC12 neuronal cells and the ability to chelate bio-metals (Zn2+, Fe2+, and Cu2+). The fraction was inactive toward acetylcholinesterase (AChE); however, it inhibited the butyrylcholinesterase (BChE) with IC50 value of 68.16 µg/mL, compared with donepezil as the reference drug (IC50 = 1.97 µg/mL) via Ellman’s method. It also showed good percentage of neuroprotection (86.28% at 100 µg/mL) against H2O2-induced neurotoxicity and moderate metal chelating ability toward Zn2+, Fe2+, and Cu2+. The phytochemical study led to isolation and identification of malabaricone A (1), malabaricone C (2), 4-(4-(3,4-dimethoxyphenyl)-2,3-dimethylbutyl)benzene-1,2-diol (3), nectandrin B (4), macelignan (5), and 4-(4-(benzo[d][1,3]dioxol-5-yl)-1-methoxy-2,3-dimethylbutyl)-2-methoxyphenol (6) which were assayed for their cholinesterase (ChE) inhibitory activity. Compounds 1 and 3 were not previously reported for M. fragrans. Among isolated compounds, compound 2 showed the best activity toward both AChE and BChE with IC50 values of 25.02 and 22.36 μM, respectively, compared with donepezil (0.07 and 4.73 μM, respectively).

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“…In the last three decades, BChE has emerged as an interesting and well-explored target in the medicinal chemistry community, especially in the fields of neurodegenerative diseases (predominantly Alzheimer's disease), bioscavanging organophosphorous nerve agents, inactivation of cocaine, heroin overdose prevention, and ghrelin-mediated effects on body weight. [1][2][3][4][5][6][7][8][9] The enzyme's active site can be separated into several defined regions: the catalytic triad (Ser198, His438, Glu325), the oxyanion hole (Gly116, Gly117, Ala199), the choline-binding pocket (Trp82), and the acylbinding pocket (Trp231, Leu286, Val288, Phe329). Near the entrance to the active site gorge is located the putative peripheral site, made of residues Asp70 and Tyr332.…”

Section: Introductionmentioning

confidence: 99%

Pseudo-irreversible butyrylcholinesterase inhibitors: SAR, kinetic, computational, and crystallographic study of the N-dialkyl O-arylcarbamate warhead

Meden

Knez

Brazzolotto³

et al. 2022

Preprint

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Beside reversible butyrylcholinesterse inhibitors (BChEIs), a plethora of covalent ones, typically pseudo-irreversible carbamates, have been reported in literature. For the latter, however, in most cases the proper confirmation of their covalent mode of action is lacking. Additionally, the available reports on the structure-activity relationships of the O-arylcarbamate warhead are incomplete. Therefore, a follow-up on a series of pseudo-irreversible covalent carbamate human butyrylcholinesterase inhibitors (hBChEIs) and the structure-activity relationships of the N-dialkyl O-arylcarbamate warhead is presented. The covalent mechanism of binding was tested by IC50 time-dependency profiles, and sequentially and increasingly confirmed by kinetic analysis, whole protein LC-MS, and crystallographic evidence. The computational studies provided valuable insights into the steric constraints and identified problematic, bulky carbamate warheads that could not reach and carbamoylate the catalytic Ser198. QM calculations lent further evidence that the steric effects seemed to be a key factor in determining the covalent binding behaviour of these carbamate ChEIs and their duration of action. Furthermore, the introduction of a clickable terminal alkyne moiety into one of the carbamate N-substituents and in situ derivatization with an azide-containing fluorophore enabled fluorescent labelling of plasma hBChE. This proof-of-concept study highlighted the potential of this novel approach and these compounds to be further developed as clickable molecular probes for investigating tissue localization and activity of ChEs.

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Butyrylcholinesterase inhibitors as potential anti-Alzheimer’s agents: an updated patent review (2018-present)

Cited by 17 publications

References 71 publications

In silico and in vitro Studies Confirm Ondansetron as a Novel Acetylcholinesterase and Butyrylcholinesterase Inhibitor

In silico and in vitro Studies Confirm Ondansetron as a Novel Acetylcholinesterase and Butyrylcholinesterase Inhibitor

Phytochemical analysis and anticholinesterase activity of aril of Myristica fragrans Houtt

Pseudo-irreversible butyrylcholinesterase inhibitors: SAR, kinetic, computational, and crystallographic study of the N-dialkyl O-arylcarbamate warhead

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