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Addressing Neurodegenerative Disorders with Monoamine Oxidase and 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 December 2023) | Viewed by 10833

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Dr. Damijan Knez

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Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
Interests: structure- and ligand-based drug design; synthesis and structure–activity relationships of biologically active compounds; multifunctional ligands; monoamine oxidase inhibitors; butyrylcholinesterase inhibitors; covalent fragments; targeted covalent inhibitors

Special Issue Information

Dear colleagues,

The continuously increasing prevalence of neurodegenerative disorders, owing in part to the prolongation of life expectancy, is becoming a worrisome global healthcare problem. No cures for illnesses such as Alzheimer’s and Parkinson’s disease currently exist, although not for lack of trying. To date, in-depth research has identified and validated numerous processes and disease-relevant targets that offer promising ways to tackle neurodegeneration. Monoamine oxidases (MAOs) and cholinesterases (ChEs) are two enzyme systems intricately related to the causes and symptoms of these disorders. The loss of cholinergic transmission is linked to impaired functions in the cognitive domain, and increasing acetylcholine levels by inhibiting ChEs, namely acetylcholinesterase and butyrylcholinesterase, which augment the cognitive decline observed in Alzheimer’s patients. Moreover, monoamine oxidase B (MAO-B) levels increase with age, leading to an increased production of reactive oxygen species among other things, which contributes to neuroinflammation and neuronal loss. With the advent of research at the cellular and subcellular levels, additional disease-related effects of MAOs and ChEs are being revealed, which further fuels the research and development of inhibitors targeting these enzymes.

Both MAOs and ChEs are clinically validated drug targets with approved drugs for the treatment of neurodegenerative diseases. New chemical entities that inhibit the single targets listed above or exert a multifunctional inhibitory profile against several targets (i.e., multifunctional ligands) are being developed using various drug design approaches. This Special Issue aims to provide a platform to share the recent advances on chemical entities that inhibit these target enzymes, and potentially show additional disease-modifying properties to address neurodegeneration.

Dr. Damijan Knez
Guest Editor

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Keywords

monoamine oxidases
cholinesterases
acetylcholinesterase
butyrylcholinesterase
drug design
enzyme inhibitors
multifunctional ligands
neurodegeneration
Alzheimer’s disease
Parkinson’s disease

Published Papers (6 papers)

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22 pages, 9690 KiB

Open AccessArticle

Thieno-Thiazolostilbenes, Thienobenzo-Thiazoles, and Naphtho-Oxazoles: Computational Study and Cholinesterase Inhibitory Activity

by Milena Mlakić, Ema Đurčević, Ilijana Odak, Danijela Barić, Ines Juričević, Ivana Šagud, Franko Burčul, Zlata Lasić, Željko Marinić and Irena Škorić

Molecules 2023, 28(9), 3781; https://doi.org/10.3390/molecules28093781 - 27 Apr 2023

Cited by 3 | Viewed by 1344

Abstract

Naphtho-triazoles and thienobenzo-triazoles have so far proven to be very potent inhibitors of the enzyme butyrylcholinesterase (BChE). Based on these results, in this work, new thienobenzo-thiazoles were designed and synthesized, and their potential inhibitory activity was tested and compared with their analogs, naphtho-oxazoles. The synthesis was carried out by photochemical cyclization of thieno-thiazolostilbenes obtained in the first reaction step. Several thienobenzo-thiazoles and naphtho-oxazoles have shown significant potential as BChE inhibitors, together with the phenolic thiazolostilbene being the most active of all tested compounds. These results are significant as BChE has been attracting growing attention due to its positive role in the treatment of Alzheimer’s disease. Computational examination based on the DFT approach enabled the characterization of the geometry and electronic structure of the studied molecules. Furthermore, the molecular docking study, accompanied by additional optimization of complexes ligand-active site, offered insight into the structure and stabilizing interactions in the complexes of studied molecules and BChE. Full article

(This article belongs to the Special Issue Addressing Neurodegenerative Disorders with Monoamine Oxidase and Cholinesterase Inhibitors)

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19 pages, 2169 KiB

Open AccessArticle

Inhibitory Activity of 4-Benzylidene Oxazolones Derivatives of Cinnamic Acid on Human Acetylcholinesterase and Cognitive Improvements in a Mouse Model

by Alma Marisol Ramírez-Ruiz, Martha Elena Ávila-Cossío, Arturo Estolano-Cobián, José Manuel Cornejo-Bravo, Ana Laura Martinez, Iván Córdova-Guerrero, Bibiana Roselly Cota-Ramírez, Krysta Paola Carranza-Ambriz, Ignacio A. Rivero and Aracely Serrano-Medina

Molecules 2023, 28(21), 7392; https://doi.org/10.3390/molecules28217392 - 2 Nov 2023

Viewed by 1027

Abstract

We synthesized seven (Z)-benzylidene-2-(E)-styryloxazol-5(4H)-ones derivatives of cinnamic acid and evaluated the ability of these compounds to inhibit human acetylcholinesterase (hAChE). The most potent compound was evaluated for cognitive improvement in short-term memory. The seven compounds reversibly inhibited the hAChE between 51 and 75% at 300 μM, showed an affinity (K_i) from 2 to 198 μM, and an IC₅₀ from 9 to 246 μM. Molecular docking studies revealed that all binding moieties are involved in the non-covalent interactions with hAChE for all compounds. In addition, in silico pharmacokinetic analysis was carried out to predict the compounds’ blood–brain barrier (BBB) permeability. The most potent inhibitor of hAChE significantly improved cognitive impairment in a modified Y-maze test (5 μmol/kg) and an Object Recognition Test (10 μmol/kg). Our results can help the rational design of hAChE inhibitors to work as potential candidates for treating cognitive disorders. Full article

(This article belongs to the Special Issue Addressing Neurodegenerative Disorders with Monoamine Oxidase and Cholinesterase Inhibitors)

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14 pages, 2367 KiB

Open AccessArticle

Rosiridin Attenuates Scopolamine-Induced Cognitive Impairments in Rats via Inhibition of Oxidative and Nitrative Stress Leaded Caspase-3/9 and TNF-α Signaling Pathways

by Muhammad Afzal, Sami I. Alzarea, Khalid Saad Alharbi, Abdulaziz I. Alzarea, Sattam Khulaif Alenezi, Mohammed Salem Alshammari, Ali H. Alquraini and Imran Kazmi

Molecules 2022, 27(18), 5888; https://doi.org/10.3390/molecules27185888 - 10 Sep 2022

Cited by 15 | Viewed by 2144

Abstract

Aim: A monoterpene and bioactive component of the plant Rhodiola rosea (R. rosea), rosiridin has beneficial effects on the human central nervous system and enhances brain function. The goal of this scientific study was to determine if rosiridin might shield rats from neurocognitive problems induced by scopolamine. Methods: To track the potential toxicities in rats, the acute toxicity in rats was clarified. Rosiridin at a dose of 10 mg/kg was tested in rats for 14 days. At the conclusion of the investigation, behavioral parameters that were used to identify the rats’ cognitive and motor abilities were evaluated. Several biochemical parameters were estimated using the prepared homogenate, including acetylcholine esterase (AChE), choline acetyltransferase (ChAT), radical scavengers produced by the body (Catalase-CAT, superoxide dismutase-SOD, and reduced glutathione-GSH), indicators of oxidative and nitrative burnout, pro-inflammatory (Interleukins- IL-1β, IL-6, interferon gamma IFN-ꝩ, and tumor necrosis factor-TNF-α), and cell apoptosis caspases 3 and 9. Results and Conclusion: A significant behavioral parameter restoration was seen in the rosiridin-treated group, including reduction in latency time during acquisition and retention trial in the Morris water maze test, and percentage of spontaneous alterations in the y-maze test, when compared to the disease control group that received scopolamine; rosiridin also altered the oxidative stress and neuroinflammatory markers, as well as restoring Ach and ChAT activities and normalizing GSH, SOD, MDA, TNF-α, nitrate, IL-1β, IL-6, IFN-ꝩ, caspases 3 and 9 levels. The results imply that rosiridin limits the effect of scopolamine on rat cognitive function. Full article

(This article belongs to the Special Issue Addressing Neurodegenerative Disorders with Monoamine Oxidase and Cholinesterase Inhibitors)

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21 pages, 5413 KiB

Open AccessArticle

Investigation on Novel E/Z 2-Benzylideneindan-1-One-Based Photoswitches with AChE and MAO-B Dual Inhibitory Activity

by Marco Paolino, Modesto de Candia, Rosa Purgatorio, Marco Catto, Mario Saletti, Anna Rita Tondo, Orazio Nicolotti, Andrea Cappelli, Antonella Brizzi, Claudia Mugnaini, Federico Corelli and Cosimo D. Altomare

Molecules 2023, 28(15), 5857; https://doi.org/10.3390/molecules28155857 - 3 Aug 2023

Cited by 3 | Viewed by 1115

Abstract

The multitarget therapeutic strategy, as opposed to the more traditional ‘one disease-one target-one drug’, may hold promise in treating multifactorial neurodegenerative syndromes, such as Alzheimer’s disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy-2,3-dihydro-1H-inden-1-one (1a), which in the E isomeric form (and about tenfold less in the UV-B photo-induced isomer Z) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs 1b–h with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound, the thermal stable E geometric isomer, along with the E/Z mixture as produced by UV-B light irradiation in the photostationary state (PSS, 75% Z), was investigated for the inhibition of human ChEs and MAOs. The pure E-isomer of the N-benzyl(ethyl)amino analog 1h achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC₅₀s 39 and 355 nM, respectively), whereas photoisomerization to the Z isomer (75% Z in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different E/Z selectivity of 1h toward the two target enzymes. Full article

(This article belongs to the Special Issue Addressing Neurodegenerative Disorders with Monoamine Oxidase and Cholinesterase Inhibitors)

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18 pages, 3870 KiB

Open AccessArticle

N-Hydroxy-N-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine Oxidases

by Óscar M. Bautista-Aguilera, José M. Alonso, Marco Catto, Isabel Iriepa, Damijan Knez, Stanislav Gobec and José Marco-Contelles

Molecules 2022, 27(21), 7437; https://doi.org/10.3390/molecules27217437 - 1 Nov 2022

Cited by 3 | Viewed by 1800

Abstract

Alzheimer’s disease (AD) is a complex disorder characterized by impaired neurotransmission in cholinergic and monoaminergic neurons, which, in combination with the accumulation of misfolded proteins and increased oxidative stress, leads to the typical features of the disease at the biomolecular level. Given the limited therapeutic success of approved drugs, it is imperative to explore rationally supported therapeutic approaches to combat this disease. The search for novel scaffolds that bind to different receptors and inhibit AD disease-related enzymes could lead to new therapeutic solutions. Here, we describe N-hydroxy-N-propargylamide hybrids 1–6, which were designed by combining the structures of Contilisant—a multifunctional anti-AD ligand—and ferulic acid, a natural antioxidant with various other biological activities. Among the synthesized compounds, we identified compound 4 as a micromolar inhibitor of hAChE with a potent radical-scavenging capacity comparable to resveratrol and Trolox. In addition, compound 4 chelated copper(II) ions associated with amyloid β pathology, mitochondrial dysfunction, and oxidative stress. The promising in vitro activity combined with favorable drug-like properties and predicted blood-brain barrier permeability make compound 4 a multifunctional ligand that merits further studies at the biochemical and cellular levels. Full article

(This article belongs to the Special Issue Addressing Neurodegenerative Disorders with Monoamine Oxidase and Cholinesterase Inhibitors)

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17 pages, 3971 KiB

Open AccessArticle

4-Phenethyl-1-Propargylpiperidine-Derived Dual Inhibitors of Butyrylcholinesterase and Monoamine Oxidase B

by Tjaša Mazej, Damijan Knez, Anže Meden, Stanislav Gobec and Matej Sova

Molecules 2021, 26(14), 4118; https://doi.org/10.3390/molecules26144118 - 6 Jul 2021

Cited by 5 | Viewed by 1974

Abstract

The multi-target-directed ligands (MTDLs) strategy is encouraged for the development of novel modulators targeting multiple pathways in the neurodegenerative cascade typical for Alzheimer’s disease (AD). Based on the structure of an in-house irreversible monoamine oxidase B (MAO-B) inhibitor, we aimed to introduce a carbamate moiety on the aromatic ring to impart cholinesterase (ChE) inhibition, and to furnish multifunctional ligands targeting two enzymes that are intricately involved in AD pathobiology. In this study, we synthesized three dual hMAO-B/hBChE inhibitors 13–15, with compound 15 exhibiting balanced, low micromolar inhibition of hMAO-B (IC₅₀of 4.3 µM) and hBChE (IC₅₀ of 8.5 µM). The docking studies and time-dependent inhibition of hBChE confirmed the initial expectation that the introduced carbamate moiety is responsible for covalent inhibition. Therefore, dual-acting compound 15 represents an excellent starting point for further optimization of balanced MTDLs Full article

(This article belongs to the Special Issue Addressing Neurodegenerative Disorders with Monoamine Oxidase and Cholinesterase Inhibitors)

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Addressing Neurodegenerative Disorders with Monoamine Oxidase and Cholinesterase Inhibitors

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