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Cholinesterase Inhibitors

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 August 2019) | Viewed by 22325

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Prof. Dr. Ludovic Jean

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Guest Editor

1. Faculty of Pharmacy, University of Paris, 4 Avenue de l'Observatoire, 75270 Paris, CEDEX 06, France
2. Laboratory CiTCoM UMR CNRS 8038, 75270 Paris, CEDEX 06, France
Interests: medicinal chemistry (reactivators of cholinesterases inhibited by organophosphorus nerve agents, inhibitors of cholinesterases and multi-targets directed ligands against neurodegenerative diseases, peptidomimetics, fluorescent probes, click chemistry)

Special Issue Information

Dear Colleagues,

Acetylcholinesterase (AChE, EC 3.1.1.7) plays a pivotal role in cholinergic transmission in the central nervous system and at the neuromuscular junctions (NMJ). Even if its physiological role has not yet been identified, butyrylcholinesterase (BChE, EC 3.1.1.8), also named pseudocholinesterase, is well known to play a role in metabolizing bioactive esters (e.g., succinylcholine, cocaine). The effects of cholinesterase inhibitors (ChEIs) have been investigated in diseases associated with a cholinergic deficit, such as Alzheimer's disease (AD) and other dementias. Although ChEIs afford mostly a symptomatic response to AD patients, the development of new ChEIs (e.g., multifunctional ligands, selective BChE inhibitors) remains of interest to treat neurodegenerative diseases. ChEIs may also be used as a treatment for an autoimmune disease named Myastenia Gravis, by targeting nicotinic acetylcholine receptors at the NMJ, and as a prophylactic treatment against organophosphorus nerve agents poisoning. On the basis of their mechanism of action, ChEIs are classified into three groups: reversible (e.g., tacrine); pseudoirreversible (e.g., rivastigmine), and irreversible (e.g., echothiophate).

In this Special Issue, we invite you to submit original research papers or reviews, which report on the design, synthesis, and biological evaluation of novel ChEIs.

Dr. Ludovic Jean
Guest Editor

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Keywords

Dementia
Myasthenia Gravis
Organophosphorus compounds
Drug discovery
Rational design

Published Papers (6 papers)

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Research

12 pages, 4489 KiB

Open AccessArticle

A Second Look at the Crystal Structures of Drosophila melanogaster Acetylcholinesterase in Complex with Tacrine Derivatives Provides Insights Concerning Catalytic Intermediates and the Design of Specific Insecticides

by Florian Nachon, Terrone L. Rosenberry, Israel Silman and Joel L. Sussman

Molecules 2020, 25(5), 1198; https://doi.org/10.3390/molecules25051198 - 06 Mar 2020

Cited by 14 | Viewed by 3249

Abstract

Over recent decades, crystallographic software for data processing and structure refinement has improved dramatically, resulting in more accurate and detailed crystal structures. It is, therefore, sometimes valuable to have a second look at “old” diffraction data, especially when earlier interpretation of the electron density maps was rather difficult. Here, we present updated crystal structures of Drosophila melanogaster acetylcholinesterase (DmAChE) originally published in [Harel et al., Prot Sci (2000) 9:1063-1072], which reveal features previously unnoticed. Thus, previously unmodeled density in the native active site can be interpreted as stable acetylation of the catalytic serine. Similarly, a strong density in the DmAChE/ZA complex originally attributed to a sulfate ion is better interpreted as a small molecule that is covalently bound. This small molecule can be modeled as either a propionate or a glycinate. The complex is reminiscent of the carboxylate butyrylcholinesterase complexes observed in crystal structures of human butyrylcholinesterases from various sources, and demonstrates the remarkable ability of cholinesterases to stabilize covalent complexes with carboxylates. A very strong peak of density (10 σ) at covalent distance from the Cβ of the catalytic serine is present in the DmAChE/ZAI complex. This can be undoubtedly attributed to an iodine atom, suggesting an unanticipated iodo/hydroxyl exchange between Ser238 and the inhibitor, possibly driven by the intense X-ray irradiation. Finally, the binding of tacrine-derived inhibitors, such as ZA (1DX4) or the iodinated analog, ZAI (1QON) results in the appearance of an open channel that connects the base of the active-site gorge to the solvent. This channel, which arises due to the absence of the conserved tyrosine present in vertebrate cholinesterases, could be exploited to design inhibitors specific to insect cholinesterases. The present study demonstrates that updated processing of older diffraction images, and the re-refinement of older diffraction data, can produce valuable information that could not be detected in the original analysis, and strongly supports the preservation of the diffraction images in public data banks. Full article

(This article belongs to the Special Issue Cholinesterase Inhibitors)

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15 pages, 4261 KiB

Open AccessArticle

Discovery of Selective Butyrylcholinesterase (BChE) Inhibitors through a Combination of Computational Studies and Biological Evaluations

by You Zhou, Xin Lu, Hongyu Yang, Yao Chen, Feng Wang, Jifu Li, Zhiran Tang, Xifei Cheng, Yingbin Yang, Li Xu and Qingyou Xia

Molecules 2019, 24(23), 4217; https://doi.org/10.3390/molecules24234217 - 20 Nov 2019

Cited by 16 | Viewed by 3260

Abstract

As there are increased levels and activity of butyrylcholiesterase (BChE) in the late stage of Alzheimer’s disease (AD), development of selective BChE inhibitors is of vital importance. In this study, a workflow combining computational technologies and biological assays were implemented to identify selective BChE inhibitors with new chemical scaffolds. In particular, a pharmacophore model served as a 3D search query to screen three compound collections containing 3.0 million compounds. Molecular docking and cluster analysis were performed to increase the efficiency and accuracy of virtual screening. Finally, 15 compounds were retained for biological investigation. Results revealed that compounds 8 and 18 could potently and highly selectively inhibit BChE activities (IC₅₀ values < 10 μM on human BChE, selectivity index BChE > 30). These active compounds with novel scaffolds provided us with a good starting point to further design potent and selective BChE inhibitors, which may be beneficial for the treatment of AD. Full article

(This article belongs to the Special Issue Cholinesterase Inhibitors)

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14 pages, 1954 KiB

Open AccessFeature PaperArticle

Synthesis and In Vitro Screening of Novel Heterocyclic β-d-Gluco- and β-d-Galactoconjugates as Butyrylcholinesterase Inhibitors

by Krešimir Baumann, Lorena Kordić, Marko Močibob, Goran Šinko and Srđanka Tomić

Molecules 2019, 24(15), 2833; https://doi.org/10.3390/molecules24152833 - 04 Aug 2019

Cited by 4 | Viewed by 3551

Abstract

The development of selective butyrylcholinesterase (BChE) inhibitors may improve the treatment of Alzheimer’s disease by increasing lower synaptic levels of the neurotransmitter acetylcholine, which is hydrolysed by acetylcholinesterase, as well as by overexpressed BChE. An increase in the synaptic levels of acetylcholine leads to normal cholinergic neurotransmission and improved cognitive functions. A series of 14 novel heterocyclic β-d-gluco- and β-d-galactoconjugates were designed and screened for inhibitory activity against BChE. In the kinetic studies, 4 out of 14 compounds showed an inhibitory effect towards BChE, with benzimidazolium and 1-benzylbenzimidazolium substituted β-d-gluco- and β-d-galacto-derivatives in a 10–50 micromolar range. The analysis performed by molecular modelling indicated key residues of the BChE active site, which contributed to a higher affinity toward the selected compounds. Sugar moiety in the inhibitor should enable better blood–brain barrier permeability, and thus increase bioavailability in the central nervous system of these compounds. Full article

(This article belongs to the Special Issue Cholinesterase Inhibitors)

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20 pages, 3375 KiB

Open AccessFeature PaperArticle

Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

by François-Xavier Toublet, Cédric Lecoutey, Julien Lalut, Bérénice Hatat, Audrey Davis, Marc Since, Sophie Corvaisier, Thomas Freret, Jana Sopkova de Oliveira Santos, Sylvie Claeysen, Michel Boulouard, Patrick Dallemagne and Christophe Rochais

Molecules 2019, 24(15), 2786; https://doi.org/10.3390/molecules24152786 - 31 Jul 2019

Cited by 17 | Viewed by 4528

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT₄ receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits. Full article

(This article belongs to the Special Issue Cholinesterase Inhibitors)

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12 pages, 3390 KiB

Open AccessFeature PaperArticle

QuinoxalineTacrine QT78, a Cholinesterase Inhibitor as a Potential Ligand for Alzheimer’s Disease Therapy

by Eva Ramos, Alejandra Palomino-Antolín, Manuela Bartolini, Isabel Iriepa, Ignacio Moraleda, Daniel Diez-Iriepa, Abdelouahid Samadi, Carol V. Cortina, Mourad Chioua, Javier Egea, Alejandro Romero and José Marco-Contelles

Molecules 2019, 24(8), 1503; https://doi.org/10.3390/molecules24081503 - 17 Apr 2019

Cited by 11 | Viewed by 3147

Abstract

We report the synthesis and relevant pharmacological properties of the quinoxalinetacrine (QT) hybrid QT78 in a project targeted to identify new non-hepatotoxic tacrine derivatives for Alzheimer’s disease therapy. We have found that QT78 is less toxic than tacrine at high concentrations (from 100 μM to 1 mM), less potent than tacrine as a ChE inhibitor, but shows selective BuChE inhibition (IC₅₀ (hAChE) = 22.0 ± 1.3 μM; IC₅₀ (hBuChE) = 6.79 ± 0.33 μM). Moreover, QT78 showed effective and strong neuroprotection against diverse toxic stimuli, such as rotenone plus oligomycin-A or okadaic acid, of biological significance for Alzheimer’s disease. Full article

(This article belongs to the Special Issue Cholinesterase Inhibitors)

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14 pages, 1584 KiB

Open AccessFeature PaperArticle

Design, Synthesis, and In Vitro Biological Activities of a Bio-Oxidizable Prodrug to Deliver Both ChEs and DYRK1A Inhibitors for AD Therapy

by Anaïs Barré, Rabah Azzouz, Vincent Gembus, Cyril Papamicaël and Vincent Levacher

Molecules 2019, 24(7), 1264; https://doi.org/10.3390/molecules24071264 - 01 Apr 2019

Cited by 6 | Viewed by 3972

Abstract

Despite their side effects, cholinesterase (ChE) inhibitors remain the only approved drugs to treat Alzheimer’s disease patients, along with the N-methyl-d-aspartate (NMDA) receptor antagonist memantine. In the last few years, the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has also been studied as a promising target for the development of new drugs for this pathology. In this context, and based on our previous characterization of bio-oxidizable prodrugs of potent acetylcholinesterase (AChE) inhibitors, we envisioned a strategy involving the synthesis of a bio-oxidizable prodrug of both ChE and DYRK1A inhibitors. To this end, we fixed our interest on a known potent inhibitor of DYRK1A, namely INDY. The designed prodrug of both ChE and DYRK1A inhibitors was successfully synthesized, connecting both inhibitors by a carbonate link. This prodrug and its corresponding drug were then evaluated as ChEs and DYRK1A inhibitors. Remarkably, in vitro results were in accordance with the starting hypothesis, showing a relative inactivity of the prodrug against DYRK1A and ChEs and a potent inhibition of ChEs by the oxidized form. Molecular docking and kinetic studies of ChE inhibition by the active compound are also discussed in this report. Full article

(This article belongs to the Special Issue Cholinesterase Inhibitors)

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