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Advances in Acetylcholinesterase and Butyrylcholinesterase Inhibitors

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 June 2023) | Viewed by 21157

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Dr. Anita Bosak

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Institute for Medical Research and Occupational Health, Zagreb, Croatia
Interests: medicinal chemistry; enzyme kinetic; structure activity relationship of acetylcholinesterase/butyrylcholinesterase inhibition; cholinesterase inhibition in termination of neurotransmission

Special Issue Information

Dear Colleagues,

The most commonly known function of acetylcholinesterase, the rapid termination of cholinergic neurotransmission via the hydrolysis of acetylcholine, whose inactivation leads to acetylcholine accumulation and the hyperstimulation of nicotinic and muscarinic receptors, means that acetylcholinesterase has been the focus of intense research of many medicinal chemists, biologists and pharmacists for decades. The gradual loss of acetylcholinesterase activity is associated with the progressive deterioration of cognitive, autonomic and neuromuscular functions, such as in Alzheimer’s disease, the most common cause of adult-onset dementia. The main class of drugs currently used for the treatment of Alzheimer’s disease are acetylcholinesterase or non-selective cholinesterase inhibitors that exert their activity and temporally improve cognitive symptoms, but they are concomitant and cause distinct side effects, and their effectiveness varies from person to person. In spite of known limitations, these drugs still represent a pharmacotherapeutic resource for the treatment of Alzheimer's disease and the type of dementia that Alzheimer's represents, often using different approaches. Generally, studies directed toward improving the pharmacological activity of cholinesterase compounds represent the mainstream in Alzheimer’s disease treatment management. In recent years, an appropriate strategy to achieve satisfactory therapeutic effect with regard to Alzheimer’s disease and related dementias has been proposed in the form of the development of multitarget-directed ligands (MTDLs) that can interact with multiple disease-related targets such as N-methyl-D-aspartate receptor antagonists or antioxidant agents, where one of the pharmacophores are directed toward the inhibition of acetylcholinesterase. Cholinesterase inhibitors are also used for the reversal of postoperative neuromuscular blockade or for the treatment of myasthenia gravis and Parkinson's disease dementia, the use of cholinesterase inhibitors was determined to have beneficial effects in cases of multiple sclerosis, traumatic brain injury and vascular dementia. On the other hand, the abrupt blockade of acetylcholinesterase action is lethal and as such has stimulated the development of organophosphate and carbamate compounds that are potent acetylcholinesterase inhibitors used as insecticides and/or chemical warfare agents. A lot of effort has been invested in the development of an effective way of returning the activity of phosphorylated acetylcholinesterase, mostly using oxime-based reactivators that are acetylcholinesterase inhibitors per se.

In the last few years, research on acetylcholinesterase’s sister enzyme, butyrylcholinesterase, has intensified due to its engagement in acetylcholine hydrolysis in the middle and late stages of Alzheimer’s disease. Additionally, many studies on the inhibition and/or reactivation of butyrylcholinesterase are devoted to finding an effective bioscavenger for treating organophosphate poisoning.

Dr. Anita Bosak
Guest Editor

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Keywords

acetylcholinesterase
butrylcholinesterase
Alzheimer’s disease
multitarget-directed ligands (MTDLs)
reversible inhibitors
irreversible inhibition
organophosphate poisoning
reactivation

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Published Papers (7 papers)

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32 pages, 5909 KiB

Open AccessArticle

Discovery of Novel Coumarin-Schiff Base Hybrids as Potential Acetylcholinesterase Inhibitors: Design, Synthesis, Enzyme Inhibition, and Computational Studies

by Aso Hameed Hasan, Faruq Azeez Abdulrahman, Ahmad J. Obaidullah, Hadil Faris Alotaibi, Mohammed M. Alanazi, Mahmoud A. Noamaan, Sankaranarayanan Murugesan, Syazwani Itri Amran, Ajmal R. Bhat and Joazaizulfazli Jamalis

Pharmaceuticals 2023, 16(7), 971; https://doi.org/10.3390/ph16070971 - 6 Jul 2023

Cited by 9 | Viewed by 2930

Abstract

To discover anti-acetylcholinesterase agents for the treatment of Alzheimer’s disease (AD), a series of novel Schiff base-coumarin hybrids was rationally designed, synthesized successfully, and structurally characterized using Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR), and High-Resolution Mass Spectrometry (HRMS) analyses. These hybrids were evaluated for their potential inhibitory effect on acetylcholinesterase (AChE). All of them exhibited excellent inhibitory activity against AChE. The IC₅₀ values ranged from 87.84 to 515.59 μg/mL; hybrids 13c and 13d with IC₅₀ values of 0.232 ± 0.011 and 0.190 ± 0.004 µM, respectively, showed the most potent activity as acetylcholinesterase inhibitors (AChEIs). The reference drug, Galantamine, yielded an IC₅₀ of 1.142 ± 0.027 µM. Reactivity descriptors, including chemical potential (μ), chemical hardness (η), electrophilicity (ω), condensed Fukui function, and dual descriptors are calculated at wB97XD/6-311++ G (d,p) to identify reactivity changes of the designed compounds. An in-depth investigation of the natural charge pattern of the studied compounds led to a deep understanding of the important interaction centers between these compounds and the biological receptors of AChE. The molecular electrostatic surface potential (MESP) of the most active site in these derivatives was determined using high-quality information and visualization. Molecular docking analysis was performed to predict binding sites and binding energies. The structure-activity-property relationship studies indicated that the proposed compounds exhibit good oral bioavailability properties. To explore the stability and dynamic behavior of the ligand-receptor complexes, molecular dynamics simulations (MDS) were performed for 100 ns on the two best docked derivatives, 13c and 13d, with the AChE (4EY7) receptor. A popular method for determining the free binding energies (MM/GBSA) is performed using snapshots taken from the systems’ trajectories at 100 ns. These results revealed that the complex system of compound 13d acquired a relatively more stable conformation and exhibited better descriptors than the complex system of compound 13c and the Galantamine drug, suggesting its potential as an effective inhibiting drug. The binding free energy analysis revealed that the 13d-4EY7 complex exhibited greater stability with AChE receptors compared to other complexes. Full article

(This article belongs to the Special Issue Advances in Acetylcholinesterase and Butyrylcholinesterase Inhibitors)

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20 pages, 2632 KiB

Open AccessArticle

Novel Inhibitors of Acetyl- and Butyrylcholinesterase Derived from Benzohydrazides: Synthesis, Evaluation and Docking Study

by Neto-Honorius Houngbedji, Šárka Štěpánková, Václav Pflégr, Katarína Svrčková, Markéta Švarcová, Jarmila Vinšová and Martin Krátký

Pharmaceuticals 2023, 16(2), 172; https://doi.org/10.3390/ph16020172 - 24 Jan 2023

Cited by 2 | Viewed by 1679

Abstract

On the basis of previous reports, novel 2-benzoylhydrazine-1-carboxamides were designed as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Inhibitors of these enzymes have many clinical applications. 2-(Substituted benzoyl)hydrazine-1-carboxamides decorated with N-methyl or tridecyl were prepared with three methods from commercially available or self-prepared hydrazides and isocyanates. For methyl derivatives, N-succinimidyl N-methylcarbamate was used or methyl isocyanate was prepared via Curtius rearrangement. Tridecyl isocyanate was synthesized again via Curtius rearrangement or from triphosgene and tridecylamine. The compounds were evaluated for the inhibition of AChE and BChE using Ellman’s spectrophotometric method. Most of the derivatives showed the dual inhibition of both enzymes with IC₅₀ values of 44–100 µM for AChE and from 22 µM for BChE. In general, the carboxamides inhibited AChE more strongly. A large number of the compounds showed better or quite comparable inhibition of cholinesterases in vitro than that of the drug rivastigmine. Molecular docking was performed to investigate the possible conformation of the compounds and their interactions with target enzymes. In both AChE and BChE, the compounds occupied the enzyme active cavity, and, especially in the case of BChE, the compounds were placed in close proximity to the catalytic triad. Full article

(This article belongs to the Special Issue Advances in Acetylcholinesterase and Butyrylcholinesterase Inhibitors)

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25 pages, 4939 KiB

Open AccessArticle

Biological Evaluation of Valeriana Extracts from Argentina with Potent Cholinesterase Inhibition for the Treatment of Neurodegenerative Disorders and Their Comorbidities—The Case of Valeriana carnosa Sm. (Caprifoliaceae) Studied in Mice

by Carolina Marcucci, Marina Rademacher, Fabiola Kamecki, Valentina Pastore, Hernán Gerónimo Bach, Rafael Alejandro Ricco, Marcelo Luis Wagner, Damijan Knez, Stanislav Gobec, Natalia Colettis and Mariel Marder

Pharmaceuticals 2023, 16(1), 129; https://doi.org/10.3390/ph16010129 - 16 Jan 2023

Cited by 3 | Viewed by 3264

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder whose pathophysiology includes the abnormal accumulation of proteins (e.g., β-amyloid), oxidative stress, and alterations in neurotransmitter levels, mainly acetylcholine. Here we present a comparative study of the effect of extracts obtained from endemic Argentinian species of valerians, namely V. carnosa Sm., V. clarionifolia Phil. and V. macrorhiza Poepp. ex DC from Patagonia and V. ferax (Griseb.) Höck and V. effusa Griseb., on different AD-related biological targets. Of these anxiolytic, sedative and sleep-inducing valerians, V. carnosa proved the most promising and was assayed in vivo. All valerians inhibited acetylcholinesterase (IC₅₀ between 1.08–12.69 mg/mL) and butyrylcholinesterase (IC₅₀ between 0.0019–1.46 mg/mL). They also inhibited the aggregation of β-amyloid peptide, were able to chelate Fe²⁺ ions, and exhibited a direct relationship between antioxidant capacity and phenolic content. Moreover, V. carnosa was able to inhibit human monoamine oxidase A (IC₅₀: 0.286 mg/mL (0.213–0.384)). A daily intake of aqueous V. carnosa extract by male Swiss mice (50 and 150 mg/kg/day) resulted in anxiolytic and antidepressant-like behavior and improved spatial memory. In addition, decreased AChE activity and oxidative stress markers were observed in treated mouse brains. Our studies contribute to the development of indigenous herbal medicines as therapeutic agents for AD. Full article

(This article belongs to the Special Issue Advances in Acetylcholinesterase and Butyrylcholinesterase Inhibitors)

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21 pages, 4892 KiB

Open AccessArticle

Identification of New N-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors

by Ashraf K. El-Damasy, Jong Eun Park, Hyun Ji Kim, Jinhyuk Lee, Eun-Kyoung Bang, Hoon Kim and Gyochang Keum

Pharmaceuticals 2023, 16(1), 83; https://doi.org/10.3390/ph16010083 - 6 Jan 2023

Cited by 9 | Viewed by 2693

Abstract

Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, seventeen N-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound 2k (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC₅₀ of 0.71 μM and selectivity index (SI) of 56.34, followed by 2n (2-fluoro-5-bromophenyl derivative) (IC₅₀ = 1.11 μM, SI = 16.04). Compounds 2k and 2n were reversible competitive MAO-B inhibitors with K_i values of 0.21 and 0.28 μM, respectively. Moreover, 2k and 2n effectively inhibited AChE with IC₅₀ of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound 2o elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC₅₀ of 1.19–3.87 μM. A cell-based assay of compounds 2k and 2n against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, 2k showed the lowest energy for MAO-B (−11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that 2k and 2n are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood–brain barrier (BBB). In view of these findings, compounds 2k and 2n could serve as promising potential candidates for the treatment of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Advances in Acetylcholinesterase and Butyrylcholinesterase Inhibitors)

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23 pages, 2472 KiB

Open AccessArticle

Design, Synthesis and Biological Evaluation of Biscarbamates as Potential Selective Butyrylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease

by Ana Matošević, Anamarija Knežević, Antonio Zandona, Nikola Maraković, Zrinka Kovarik and Anita Bosak

Pharmaceuticals 2022, 15(10), 1220; https://doi.org/10.3390/ph15101220 - 30 Sep 2022

Cited by 7 | Viewed by 2463

Abstract

As butyrylcholinesterase (BChE) plays a role in the progression of symptoms and pathophysiology of Alzheimer’s disease (AD), selective inhibition of BChE over acetylcholinesterase (AChE) can represent a promising pathway in treating AD. The carbamate group was chosen as a pharmacophore because the carbamates currently or previously in use for the treatment of AD displayed significant positive effects on cognitive symptoms. Eighteen biscarbamates with different substituents at the carbamoyl and hydroxyaminoethyl chain were synthesized, and their inhibitory potential toward both cholinesterases and inhibition selectivity were determined. The ability of carbamates to cross the blood–brain barrier (BBB) by passive transport, their cytotoxic profile and their ability to chelate biometals were also evaluated. All biscarbamates displayed a time-dependent inhibition with inhibition rate constants within 10⁻³–10⁻⁶ M⁻¹ min⁻¹ range for both cholinesterases, with generally higher preference to BChE. For two biscarbamates, it was determined that they should be able to pass the BBB by passive transport, while for five biscarbamates, this ability was slightly limited. Fourteen biscarbamates did not exhibit a cytotoxic effect toward liver, kidney and neuronal cells. In conclusion, considering their high BChE selectivity, non-toxicity, ability to chelate biometals and pass the BBB, compounds 2 and 16 were pointed out as the most promising compounds for the treatment of middle and late stages of AD. Full article

(This article belongs to the Special Issue Advances in Acetylcholinesterase and Butyrylcholinesterase Inhibitors)

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21 pages, 1273 KiB

Open AccessArticle

Synthesis, Biological Evaluation and Machine Learning Prediction Model for Fluorinated Cinchona Alkaloid-Based Derivatives as Cholinesterase Inhibitors

by Alma Ramić, Ana Matošević, Barbara Debanić, Ana Mikelić, Ines Primožič, Anita Bosak and Tomica Hrenar

Pharmaceuticals 2022, 15(10), 1214; https://doi.org/10.3390/ph15101214 - 30 Sep 2022

Cited by 1 | Viewed by 1846

Abstract

A series of 46 Cinchona alkaloid derivatives that differ in positions of fluorine atom(s) in the molecule were synthesized and tested as human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. All tested compounds reversibly inhibited AChE and BChE in the nanomolar to micromolar range; for AChE, the determined enzyme-inhibitor dissociation constants (K_i) ranged from 3.9–80 µM, and 0.075–19 µM for BChE. The most potent AChE inhibitor was N-(para-fluorobenzyl)cinchoninium bromide, while N-(meta-fluorobenzyl)cinchonidinium bromide was the most potent BChE inhibitor with K_i constant in the nanomolar range. Generally, compounds were non-selective or BChE selective cholinesterase inhibitors, where N-(meta-fluorobenzyl)cinchonidinium bromide was the most selective showing 533 times higher preference for BChE. In silico study revealed that twenty-six compounds should be able to cross the blood-brain barrier by passive transport. An extensive machine learning procedure was utilized for the creation of multivariate linear regression models of AChE and BChE inhibition. The best possible models with predicted R² (CD-derivatives) of 0.9932 and R²(CN-derivatives) of 0.9879 were calculated and cross-validated. From these data, a smart guided search for new potential leads can be performed. These results pointed out that quaternary Cinchona alkaloids are the promising structural base for further development as selective BChE inhibitors which can be used in the central nervous system. Full article

(This article belongs to the Special Issue Advances in Acetylcholinesterase and Butyrylcholinesterase Inhibitors)

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Review

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43 pages, 21793 KiB

Open AccessReview

An Overview of 1,2,3-triazole-Containing Hybrids and Their Potential Anticholinesterase Activities

by Shah Alam Khan, Mohammad Jawaid Akhtar, Urvashee Gogoi, Dhanalekshmi Unnikrishnan Meenakshi and Aparoop Das

Pharmaceuticals 2023, 16(2), 179; https://doi.org/10.3390/ph16020179 - 24 Jan 2023

Cited by 28 | Viewed by 3992

Abstract

Acetylcholine (ACh) neurotransmitter of the cholinergic system in the brain is involved in learning, memory, stress responses, and cognitive functioning. It is hydrolyzed into choline and acetic acid by two key cholinesterase enzymes, viz., acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A loss or degeneration of cholinergic neurons that leads to a reduction in ACh levels is considered a significant contributing factor in the development of neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD). Numerous studies have shown that cholinesterase inhibitors can raise the level of ACh and, therefore, enhance people’s quality of life, and, at the very least, it can temporarily lessen the symptoms of NDs. 1,2,3-triazole, a five-membered heterocyclic ring, is a privileged moiety, that is, a central scaffold, and is capable of interacting with a variety of receptors and enzymes to exhibit a broad range of important biological activities. Recently, it has been clubbed with other pharmacophoric fragments/molecules in hope of obtaining potent and selective AChE and/or BuChE inhibitors. The present updated review succinctly summarizes the different synthetic strategies used to synthesize the 1,2,3-triazole moiety. It also highlights the anticholinesterase potential of various 1,2,3-triazole di/trihybrids reported in the past seven years (2015–2022), including a rationale for hybridization and with an emphasis on their structural features for the development and optimization of cholinesterase inhibitors to treat NDs. Full article

(This article belongs to the Special Issue Advances in Acetylcholinesterase and Butyrylcholinesterase Inhibitors)

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