Potent Cholinesterase Inhibitor Research Articles

Cholinesterase Inhibitory Potential of Quercetin towards Alzheimer's Disease - A Promising Natural Molecule or Fashion of the Day? - A Narrowed Review.

Natural substances are known to have strong protective effects against neurodegenerative diseases. Among them, phenolic compounds, especially flavonoids, come to the fore with their neuroprotective effects. Since quercetin, which is found in many medicinal plants and foods, is also taken through diet, its physiological effects on humans are imperative. Many studies have been published up to date on the neuroprotective properties of quercetin, a flavanol derivative. However, there is no review published so far summarizing the effect of quercetin on the cholinesterase (ChE) enzymes related to the cholinergic hypothesis, which is one of the pathological mechanisms of Alzheimer's Disease (AD). However, ChE inhibitors, regardless of natural or synthetic, play a vital role in the treatment of AD. Although the number of studies on the ChE inhibitory effect of quercetin is limited, it deserves to be discussed in a review article. With this sensitivity, the neuroprotective effect of quercetin against AD through ChE inhibition was scrutinized in the current review study. In addition, studies on the bioavailability of quercetin and its capacity to cross the blood-brain barrier and how this capacity and bioavailability can be increased were given. Generally, studies containing data published in recent years were obtained from search engines such as PubMed, Scopus, and Medline and included herein. Consequently, quercetin should not be considered as a fashionable natural compound and should be identified as a promising compound, especially with increased bioavailability, for the treatment of AD.

Social Isolation: How Can the Effects on the Cholinergic System Be Isolated?

Social species form organizations that support individuals because the consequent social behaviors help these organisms survive. The isolation of these individuals may be a stressor. We reviewed the potential mechanisms of the effects of social isolation on cholinergic signaling and vice versa how changes in cholinergic signaling affect changes due to social isolation.There are two important problems regarding this topic. First, isolation schemes differ in their duration (1–165 days) and initiation (immediately after birth to adulthood). Second, there is an important problem that is generally not considered when studying the role of the cholinergic system in neurobehavioral correlates: muscarinic and nicotinic receptor subtypes do not differ sufficiently in their affinity for orthosteric site agonists and antagonists. Some potential cholinesterase inhibitors also affect other targets, such as receptors or other neurotransmitter systems. Therefore, the role of the cholinergic system in social isolation should be carefully considered, and multiple receptor systems may be involved in the central nervous system response, although some subtypes are involved in specific functions. To determine the role of a specific receptor subtype, the presence of a specific subtype in the central nervous system should be determined using search in knockout studies with the careful application of specific agonists/antagonists.

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer's Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC50 value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC50 = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer’s disease.

Neuroprotective potentials of selected natural edible oils using enzyme inhibitory, kinetic and simulation approaches

BackgroundEdible oils have proven health benefits in the prevention and treatment of various disorders since the establishment of human era. This study was aimed to appraise neuropharmacological studies on the commonly used edible oils including Cinnamomum verum (CV), Zingiber officinale (ZO) and Cuminum cyminum (CC).MethodsThe oils were analyzed via GC-MS for identifications of bioactive compounds. Anti-radicals capacity of the oils were evaluated via 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radicals scavenging assays. The samples were also tested against two important acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are among the important drug targets in Alzheimer’s disease. Lineweaver-Burk plots were constructed for enzyme inhibition studies which correspond to velocity of enzymes (Vmax) against the reciprocal of substrate concentration (Km) in the presence of test samples and control drugs following Michaelis-Menten kinetics. Docking studies on AChE target were also carried out using Molecular Operating Environment (MOE 2016.0802) software.Results(Gas chromatography-mass spectrometry GC-MS) analysis revealed the presence of thirty-four compounds in Cinnamon oil (Cv.Eo), fourteen in ginger oil (Zo.Eo) and fifty-six in cumin oil (Cc.Eo). In the antioxidant assays, Cv.Eo, Zo.Eo and Cc.Eo exhibited IC50 values of 85, 121, 280 μg/ml sequentially against DPPH radicals. Whereas, in ABTS assay, Cv.Eo, Zo.Eo and Cc.Eo showed considerable anti-radicals potentials with IC50 values of 93, 77 and 271 μg/ml respectively. Furthermore, Cv.Eo was highly active against AChE enzyme with IC50 of 21 μg/ml. Zo.Eo and Cc.Eo exhibited considerable inhibitory activities against AChE with IC50 values of 88 and 198 μg/ml respectively. In BChE assay, Cv.Eo, Zo.Eo and Cc.Eo exhibited IC50 values of 106, 101 and 37 μg/ml respectively. Our results revealed that these oils possess considerable antioxidant and cholinesterase inhibitory potentials. As functional foods these oils can be effective remedy for the prevention and management of neurological disorders including AD. Synergistic effect of all the identified compounds was determined via binding energy values computed through docking simulations. Binding orientations showed that all the compounds interact with amino acid residues present in the peripheral anionic site (PAS) and catalytic anionic site (CAS) amino acid residues, oxyanion hole and acyl pocket via π-π stacking interactions and hydrogen bond interactions.

Evaluation of selected carotenoids of Lycopersicon esculentum variants as therapeutic targets for \u2018Alzheimer\u2019s disease: an in silico approach

The seriousness and menace of the worldwide weight of ‘Alzheimer’s disease have been related to a few factors, which incorporate antioxidant system depletion, mutation of proteins, and high expression of cholinesterases due to aging, environmental influence, diet, infectious agents, and hormonal imbalance. Overexpression of cholinesterases has been emphatically connected to ‘Alzheimer’s disease because of the unreasonable hydrolysis of acetylcholine and butyrylcholine. Certain plant phytochemicals, for example, beta-carotenoids, lutein, neoxanthin, and viola-xanthine from Lycopersicon esculentum Mill. Var. esculentum (ESC) and Lycopersicon esculentum Mill. Var. cerasiforme (CER) has been utilized altogether as a therapeutic candidate for the treatment of ‘Alzheimer’s disease. Therefore, this research sought to investigate the drug-likeness of the individual carotenoids as detailed for cholinesterase inhibition in the treatment of ‘Alzheimer’s disease. Four potential cholinesterase inhibitors from ESC and CER were retrieved from the PubChem database. Investigation of their drug-likeness, toxicity prediction, molecular docking, and dynamic simulations were carried out using Molinspiration, PreADMET V.2.0, Patchdock server, and Schrodinger Maestro software respectively. Neoxanthin was ranked the safest with a greater tendency to inhibit the cholinesterases with high binding affinity. In addition, its stability after simulation in a mimicked biological environment suggests its relevance as a potential drug candidate for the treatment of ‘Alzheimer’s disease through the inhibition of cholinesterases.

New Coumarin-Pyrazole hybrids: Synthesis, Docking studies and Biological evaluation as potential cholinesterase inhibitors

A new set of hybrid derivatives bearing pyrazole and coumarin scaffold 3a-f was synthesized and confirmed by different spectroscopic techniques (1H NMR, 13C NMR, FT-IR) and mass spectrometry. This study aimed to evaluate the inhibitory activity of new derivatives against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using Galanthamine as standard drugs. In vitro studies showed that compounds 3e and 3f were the most effective showing high potential AChE inhibitory activities with respective IC50 values of 4.41±0.53 and 5.04±0.96 µg/ml. Compounds 3a and 3b were found to be the best butyrylcholinesterase inhibitor with an IC50 value comparable to that of the standard drugs. All the newly synthesized derivatives 3a–f are evaluated for their antioxidant activity and showed good activity. Molecular docking study was also carried to get insights into binding interactions of synthesized compounds to act as AChE and BChE inhibitors. The docking study of compound 3e with AChE enzyme showed that PAS are occupied by the ligand. In silico predictions of toxicity analysis indicated that these compounds should have good oral bioavailability.

Synthesis, molecular docking and molecular dynamics studies of novel tacrine-carbamate derivatives as potent cholinesterase inhibitors

In the present study, new tacrine derivatives containing carbamate group were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition activities were evaluated. All synthesized compounds inhibited both cholinesterases at nanomolar level. Among them, ((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl(3-nitrophenyl) carbamate (6k) showed the best inhibitor activity against AChE and BuChE with IC50 value of 22.15 nM and 16.96 nM, respectively. The calculated selectivity index revealed that the synthesized compounds (exclude 6l) have stronger inhibitory activity against BuChE than AChE. The most selective compound was 2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl(4-methoxyphenyl)-carbamate (6b) with the selectivity index of 0.12. Molecular modeling approaches were employed to understand the interaction between the synthesized compounds and proteins. As carbamate derivatives can act as pseudo-irreversible inhibitors of AChE and BuChE, covalent docking approaches was applied to determine the binding modes of novel compounds at binding sites of cholinesterase enzymes.

Evaluation of cholinesterase inhibitory and antioxidant activity of Wedelia chinensis and isolation of apigenin as an active compound

BackgroundWedelia chinensis has been reported as a folk medicine for the treatment of different diseases including neurodegenerative disease. Although the plant has been studied well for diverse biological activities, the effect of this plant in neurological disorder is largely unknown. The present study was undertaken to evaluate the cholinesterase inhibitory and antioxidant potential of W. chinensis.MethodsThe extract and fractions of the plant were evaluated for acetylcholinesterase and butyrylcholinesterase inhibitory activity by modified Ellman method. The antioxidant activity was assessed in several in vitro models/assays such as reducing power, total antioxidant capacity, total phenolic and flavonoid content, scavenging of 2,2′-diphenyl-1-picrylhydrazyl (DPPH) free radical and hydroxyl radical, and inhibition of brain lipid peroxidation. Chromatographic and spectroscopic methods were used to isolate and identify the active compound from the extract.ResultsAmong the fractions, aqueous fraction (AQF) and ethylacetate fraction (EAF) exhibited high inhibition against acetylcholinesterase (IC50: 40.02 ± 0.16 μg/ml and 57.76 ± 0.37 μg/ml) and butyrylcholinesterase (IC50: 31.79 ± 0.18 μg/ml and 48.41 ± 0.05 μg/ml). Similarly, the EAF and AQF had high content of phenolics and flavonoids and possess strong antioxidant activity in several antioxidant assays including DPPH and hydroxyl radical scavenging, reducing power and total antioxidant activity. They effectively inhibited the peroxidation of brain lipid in vitro with IC50 values of 45.20 ± 0.10 μg/ml and 25.53 ± 0.04 μg/ml, respectively. A significant correlation was observed between total flavonoids and antioxidant and cholinesterase inhibitory activity. Activity guided chromatographic separation led to the isolation of a major active compound from the EAF and its structure was elucidated as apigenin by spectral analysis.ConclusionsThe potential ability of W. chinensis to inhibit the cholinesterase activity and peroxidation of lipids suggest that the plant might be useful for the management of AD.

P-MD005. Neuroprotective effects of gossypetin in alzheimer's disease: Therapeutic approaches to evaluate the acetylcholinesterase and butyl cholinesterase inhibitory potential

Introduction. Phytochemical present in medicinal plants have been used for the treatment of numerous human health complication. Phytochemical can be categorized into different chemical classes including flavonoidal compounds which are well known in the medicine for their anti-cancer, anti-oxidant, anti-aging and anti-inflammatory activity. Gossypetin is pure phytochemical found to be present in the numerous medicinal plants including Hibiscus species. Methods. Biological importances of gossypetin in the treatment of Alzheimer’s disease were studied in the present investigation to know their effectiveness against acetylcholinesterase and butyl cholinesterase (AChE and BuChE) through scientific database analysis of different research work of the scientific fields. Present investigation revealed the biological importance and therapeutic benefit of gossypetin in medicine and other allied health sectors. In order to know the medicinal importance of gossypetin in brain related disorder, here in the present investigation therapeutic benefit of gossypetin on cholinesterase enzymes such as AChE and BuChE were investigated through scientific data analysis of different In-silico research work of the literature. Experimental works have been performed to know the benefit of gossypetin in the medicine. Results. Scientific data analysis of different research work of the literature signified the biological importance of gossypetin in the medicine due to their significant antioxidant potential. Scientific research work data analysis revealed their effectiveness against various form of cancerous disorders such as breast cancer and hepatocellular cancer. Molecular docking study revealed the biological importance of AChE and BuChE enzymes in the brain related disorders. Molecular docking study also signified the probable mode of interaction and binding modes of inhibition of AchE and BuChE enzymes. Research work of different scientific field also revealed the biological importance of hydrophobic interaction in the stability of complex. Conclusions. Present investigation signified the therapeutic benefit of gossypetin for the treatment of Alzheimer's disease through interaction of cholinesterase enzymes.

Understanding the phytochemistry and molecular insights to the pharmacology of Angelica archangelica L. (garden angelica) and its bioactive components.

Plant-derived molecules have enduring usefulness in treating diseases, and herbal drugs have emerged as a vital component of global therapeutic demand. Angelica archangelica L. (A. archangelica), commonly known as garden angelica, is an aromatic food plant used in culinary procedures as a flavoring agent. In the traditional medicine system, it is regarded as an "Angel plant" due to its miraculous curative power. This review aims to provide a comprehensive summary of the plant's taxonomic profile, ethnopharmacology, Phytochemistry, and pharmacological activities. Various in vivo and in vitro experiments have validated that the plant possesses broad pharmacological potential. The biological activities attributed to the plant include anti-anxiety activity, anti-convulsant activity, cognition enhancer, antiviral activity, cholinesterase inhibitory potential, antiinflammatory activity, gastroprotective activity, and radioprotective activity. The beneficial effects of the plant are credited to its bioactive components, that is, coumarins and volatile oils. The review summarizes the pharmacological activities of crude extract and its bioactive fractions and has also explored their target-oriented effects. This review will be of value in undertaking further investigations on the plant with regard to exploring mechanism-based pharmacological approaches on A. archangelica.

Green Synthesis, Characterization and Cholinesterase Inhibitory Potential of Gold Nanoparticles

Abstract. The green synthesis of gold nanoparticles (Au NPs) from their precursor was carried out using Delphinium uncinatum and Erythrophyleum guineense plants extracts. The Au NPs obtained were characterized by various instrumental techniques such as scanning electron microscopy (SEM), energy dispersive X-ray (EDX), X-ray diffraction (XRD) and UV/Visible (UV/VIS) spectrophotometer. The SEM study presented that E. guineense (GE) and D. uncinatum (GN) synthesized gold nanoparticles was below 100 and 300 nm, respectively. The micrographs also presented that E. guineense (GE) synthesized gold particles had irregular round shaped while the D. uncinatum (GN) synthesized nanoparticles had cylindrical shaped. The XRD spectra presented peaks at about 38.1°, 44.43°, 64.6° and 77.64° can be indexed to (111), (200), (220) and (311) orientation, respectively, which confirmed the presence of gold nanoparticles. It means that both E. guineense (GE) and D. uncinatum (GN) synthesized gold nanoparticles are highly crystalline. The UV/VIS analysis presented that both plant extracts significantly reduced the gold slat and as a result high quantity of gold nanoparticles were formed. The E. guanense gold NP and D. uncinatum gold NPs were investigated for their in-vitro cholinesterases inhibitory potentials in 62.5-1000 µg/mL concentrations range. The bioactivity results presented that the loading of the test samples in gold NPs enhanced their AChE and BChE inhibitory potentials.
 
 Resumen. La síntesis verde de nanopartículas de oro (NP de Au) se llevó a cabo mediante extractos de plantas de Delphinium uncinatum y Erythrophyleum guineense. Las NP de Au obtenidas se caracterizaron mediante diversas técnicas instrumentales como microscopía electrónica de barrido (SEM), dispersión de energía de rayos X (EDX), difracción de rayos X (XRD) y espectrofotómetro UV / Visible (UV / Vis). El estudio SEM reveló tamaños de las nanopartículas de oro sintetizadas por E. guineense (GE) y D. uncinatum (GN) por debajo de 100 y 300 nm, respectivamente. Las micrografías también mostraron que las partículas de oro sintetizadas por E. guineense (GE) tenían una forma redonda irregular, mientras que las nanopartículas sintetizadas por D. uncinatum (GN) tenían una forma cilíndrica. Los patrones XRD presentaron picos a aproximadamente 38.1 °, 44.43 °, 64.6 ° y 77.64 ° pueden indexarse ​​a la orientación (111), (200), (220) y (311), respectivamente, lo que confirmó la presencia de nanopartículas de oro cristalinas. El análisis UV / Vis mostró que ambos extractos de plantas formaron nanopartículas de oro. Se investigaron las NP de oro como inhibidores de colinesterasas in vitro en un intervalo de concentraciones de 62.5 a 1000 µg / ml. Los resultados de la bioactividad mostraron que la carga de las muestras de prueba en NP de oro mejoró sus potenciales inhibidores de AChE y BChE.

Evaluation of chemical constituents and biological properties of two endemic Verbascum species

Members from the Verbascum genus are well appraised for their traditional uses against a variety of ailments including anti-inflammatory related disorders. This study thus attempts at validating the biological properties of two underexplored Verbascum members namely Verbascum euphraticum Benth. (V. euphraticum) and Verbascum oocarpum Murb. (V. oocarpum) in terms of their antioxidant and enzymatic inhibitory activities. Concentration of specific bioactive compounds was also established and molecular dynamic analysis were conducted on amassed data. Results showed that total phenolic and total flavonoid contents were higher for the methanolic extract of V. oocarpum compared to the methanolic extract of V. euphraticum. Phytochemical quantification revealed that the extraction solvents influenced the phytochemical composition of the extracts. Derivatives of phenolic acids such as 3-caffeoylquinic acid and 3,5-dicaffeoylquinic acid together with some phenolic acids i.e., gallic, vanillic, caffeic, syringic, p-coumaric and ferulic acid, have been detected in the extracts of both Verbascum species. Methanolic extracts of V. euphraticum and V. oocarpum yielded the highest total content of monitored compounds resulting in 162.758 and 3716.861 μg/g of dried weight extract, respectively. The methanolic extracts of both plants showed highest antioxidant potential while the ethyl acetate and hexane extracts were potent inhibitors of cholinesterase, α-amylase and α-glucosidase. Molecular dynamic results indicated that vanillic acid is able to make strong interactions with copper ions of tyrosinase, resulting into an effective anti-tyrosinase activity. In light of the above, both Verbascum species could be considered for future phytopharmaceutical development.

1H-1,2,3-triazole grafted tacrine-chalcone conjugates as potential cholinesterase inhibitors with the evaluation of their behavioral tests and oxidative stress in mice brain cells

The present paper explicates the synthesis of 1H-1,2,3-triazole tethered tacrine-chalcone conjugates and evaluation of their AChE and BuChE inhibitory activity. In-vitroAChE inhibition assay revealed three compounds, 9h, 9i, and 11f, being more potent than the standard drug tacrine and further evaluated against butyrylcholinesterase. The present study was extended to investigate the anti-amnestic effect of promising compoundson scopolamine-induced behavioral and neurochemical changes in mice. Inclined plane model and Elevated plus-maze model were performed to assess general limb motor activity and anxiety-like behavior, respectively, in mice pre-treated with scopolamine. Oxidative stress parameters reduced glutathione contents (GSH) and lipid peroxidation products (TBARS) in the brain homogenates as estimated using ex-vivo studies. Furthermore, molecular docking studies were performed for the potent compounds to decipher the mechanism of observed activities.

In Vitro Enzymatic and Kinetic Studies, and In Silico Drug-Receptor Interactions, and Drug-Like Profiling of the 5-Styrylbenzamide Derivatives as Potential Cholinesterase and β-Secretase Inhibitors with Antioxidant Properties.

The 5-(styryl)anthranilamides were transformed into the corresponding 5-styryl-2-(p-tolylsulfonamido)benzamide derivatives. These 5-styrylbenzamide derivatives were evaluated through enzymatic assays in vitro for their capability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE-1) activities as well as for antioxidant potential. An in vitro cell-based antioxidant activity assay involving lipopolysaccharides (LPS)-induced reactive oxygen species (ROS) production revealed that compounds 2a and 3b have the capability of scavenging free radicals. The potential of the most active compound, 5-styrylbenzamide (2a), to bind copper (II) or zinc (II) ions has also been evaluated spectrophotometrically. Kinetic studies of the most active derivatives from each series against the AChE, BChE, and β-secretase activities have been performed. The experimental results are complemented with molecular docking studies into the active sites of these enzymes to predict the hypothetical protein–ligand binding modes. Their drug likeness properties have also been predicted.

Lipase-catalysed one-pot synthesis of thiazole-based Betti bases and their evaluation as potential cholinesterase inhibitors

A series of 1-[aryl-(thiazol-2-ylamino)-methyl]-naphthalen-2-ol derivatives were synthesized using porcine pancreatic lipase as a catalyst. The major assets of this methodology were use of biocatalyst, non-toxic organic medium, mild reaction condition and good-to-excellent yield of desired products. The synthesized Betti bases were evaluated for in vitro anti-cholinesterase activity. Test compounds exhibited potential inhibitory activities towards AChE (IC50 = 0.82 to 4.27 µM) as well as BuChE (IC50 = 2.18 to 9.64 µM). Compound 4g exhibited highest inhibitory activity for both AChE (IC50 = 0.82 ± 0.05 µM) and BuChE (IC50 = 2.18 ± 0.21 µM) when compared to standard reference drug galantamine inferring that it acts a dual AChE/BuChE inhibitor. Kinetic studies of compound 4g suggested a mixed-type inhibition towards both AChE and BuChE with Ki values of 8.82 μM and 12.41 μM, respectively. Further, cell viability assay that compound 4(a–j) do not impart any toxicity to N2a cells. In addition, molecular docking studies were performed to corroborate the biological results. This is the first report on lipase-catalysed synthesis of Betti bases as well as for their potential in vitro anti‐Alzheimer activity.

Azole antifungal compounds could have dual cholinesterase inhibitory potential according to virtual screening, enzyme kinetics, and toxicity studies of an inhouse library

Recent advances in cholinesterase inhibitors opened new venues for the treatment of cognitive disorders like Alzheimer's disease. Certain azole antifungals like miconazole were reported to have cholinesterase inhibitory effects and hence ameliorate cognitive deficits. In this study, we tested a set of azole antifungal derivatives selected through virtual screening of an inhouse library for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory effects. Compound 61 showed potent and selective AChE inhibition (IC50 = 8.77 µM). The study also yielded dual AChE/BChE inhibitors in addition to a number of potent AChE inhibitors. Enzyme kinetics assays revealed that AChE inhibitors were competitive inhibitors. All the active compounds were imidazole derivatives and the modeling study showed that imidazole at protonated state contributed greatly to the binding interactions with some key residues of AChE and BChE active site. The active derivatives had negligible cytotoxic effects on murine fibroblast viability. According to our results, compounds featuring the classical scaffold of azole antifungal drugs could hold high potential for anticholinesterase drug design.

Synthesis and Bio-Evaluation of N-Benzylpiperidine-8-Hydroxyquinoline Derivatives as Potential Cholinesterase Inhibitors, Metal Ion Chelators and Calcium Channel Blockers

Synthesis and Bio-Evaluation of N-Benzylpiperidine-8-Hydroxyquinoline Derivatives as Potential Cholinesterase Inhibitors, Metal Ion Chelators and Calcium Channel Blockers

Design, synthesis and evaluation of dihydropyranoindole derivatives as potential cholinesterase inhibitors against Alzheimer’s disease

A series of novel dihydropyranoindole derivatives containing sulphonamide group were designed, synthesized and evaluated for in-vitro anti-cholinesterase activity. The result showed that all the compounds exhibited potent acetylcholinesterase (AChE) activity (IC50 = 0.41–8.79 µM) while demonstrated moderate to good activity for butyrylcholinesterase (BuChE) (IC50 = 1.17–30.17 µM). The tested compounds exhibited selectivity towards AChE over BuChE. Compound 5o was most potent towards both AChE (IC50 = 0.41 µM) and BuChE (IC50 = 1.17 µM) when compared to standard galantamine and rivastigmine. Enzyme kinetics and molecular docking studies revealed that compound 5o shows mixed type inhibition and binds to peripheral anionic site (PAS) and the catalytic sites (CAS) of both the enzymes. Furthermore, cell viability studies were also performed against N2a cells along with neuroprotection studies against H2O2 in the same cell line. Antioxidant studies using DPPH radical and H2O2 were also performed which revealed that all compounds possessed some antioxidant activity. Also, DNA damage protection assay for compound 5o was performed implying that compound 5o was protective in nature. ADME studies were also performed which demonstrated good pharmacokinetics. These findings indicated that dihydropyranoindole derivatives could be possible drug lead in the search for new multifunctional AD drugs.

Bis (Diamines) Cu and Zn Complexes of Flurbiprofen as Potential Cholinesterase Inhibitors: In Vitro Studies and Docking Simulations

Alzheimer’s disease (AD) causes dementia and continuous damage to brain cells. Cholinesterase inhibitors can alleviate the condition by increasing communication between the nerve cells and reducing the risk of dementia. In an effort to treat Alzheimer’s disease, we synthesized flurbiprofen-based diamines (1,2 diaminoethane and 1,3 diaminopropane) Zn(II), Cu(II) metal complexes and characterized them by single-crystal X-ray analysis, NMR, (FT)-IR, UV-Vis, magnetic susceptibility, elemental analysis and conductivities measurements. Synthesized diamine metal complexes appeared in ionic forms and have distorted octahedral geometry based on conductivity studies, magnetic susceptibility and electronic studies. Single crystal X-ray diffraction analysis confirmed (2b) Cu(H2O)2(L1)2(L2)2 complex formation. Moreover, we tested all synthesized metal complexes against the cholinesterase enzyme that showed higher inhibition potential. In general, copper metal complexes showed higher inhibitory activities than simple metal complexes with flurbiprofen. These synthesized metal complexes may derive more effective and safe inhibitors for cholinesterases.

Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer’s heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target N-heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC50 values less than 20 μM. N-(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC50 values of 9.68 and 11.59 μM, respectively. Various informative structure–activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.