Active Site Of AChE Research Articles

Insight from Molecular Modeling and ADMET analysis: Design, Synthesis and In Vitro Acetylcholinesterase and Butyrylcholinesterase Assessment of Thiazolidinone Containing Benzoxazole Hybrids Derivatives

Alzheimer's disease (AD) is a brain disorder medically defined as loss of memory and analytical reasoning abilities of an infected person. The adult or aged peoples are more likely to be adversely affected by this disease. Following this prospect, this study is conducted to synthesize a novel class of (Z)-2-(((Z)-2-(benzo[d]oxazol-2-ylthio)-1-phenylethylidene)hydrazono)-3-phenylthiazolidin-4-one based derivatives and evaluate its performance towards the treatment of AD. This study showed the better results when compared to the inhibition potential of the standard drug Donepezil against AChE (IC50= 4.10 ± 1.05 µM) and against BuChE (IC50=6.59 ± 1.63 µM), the inhibition potential shown by benzimidazole based thiadiazole scaffolds against the targeted enzymes is of wide range. The inhibition potential of all the scaffolds against AChE ranged from 2.89 ± 0.65 µM to 19.04 ± 0.49 µM and against BuChE ranged from 3.70 ± 0.98 µM to 23.19 ± 0.71 µM. Moreover, to investigate the binding interaction of effective scaffolds against the active sites of AChE and BuChE, molecular docking studies were carried out and the analysis data evaluated the substantial binding interaction of scaffolds against the targeted enzymes. The structural characteristic of each scaffold is determined by using different spectroscopic techniques. In this work only three analogues found to be the most active having the observed IC50 values 7d, 3.05 ± 0.19 µM, 2.90 ± 0.87 µM(for BuChE), 7g, 3.88 ± 0.32 µM(for AChE), 4.98 ± 0.54 µM(for BuChE), 7k 2.89 ± 0.65 µM(for AChE), 3.70 ± 0.98 µM(for BuChE). Furthermore, the selected analogues considered for In-Vivo and cytotoxic study as well as structure modification carried out in search of more active analogues.

New Sulfonate Ester-Linked Fluorinated Hydrazone Derivatives as Multitarget Carbonic Anhydrase and Cholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, Molecular Docking and ADME Analysis.

In this study, some new hydrazone derivatives (2a-g) was designed, synthesized for first time, and evaluated as multitarget inhibitors of AChE, BChE, hCA I and hCA II. The chemical structures of new hybrids were confirmed by elemental analysis and some spectroscopic techniques. All tested compounds showed low nanomolar inhibition with IC50 values of in the range of 30.4-264.0 nM against hCA I, 23.2-251.6 nM against hCA II, 12.1-114.3 nM against AChE, and 76.4-134.0 nM against BChE. These compounds inhibited hCA I and AChE more than acetazolamide (AZA) and neostigmine. Among them, compounds 2c and 2e, which have a linear structure, were determined to be the most active inhibitor candidates against these selected enzymes. Molecular docking studies were carried out on the compounds (2a--g), revealing their binding interactions with the active site of AChE, BChE, hCA I and hCA II thus supporting the experimental findings. Additionally, in silico absorption, distribution, metabolism, and excretion (ADME) prediction studies of the obtained compounds (2a--g) with in silico approaches were carried out to determine their solubility, whether they have the potential to cross the blood-brain barrier (BBB), values such as GI absorption and drug likeness principles.

New 1,2,4-oxadiazole derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease: design, synthesis, and biological evaluation

A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC50 = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC50 values in the range of 16.64–70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC50 = 5.88 µM). Moreover, oxadiazole derivative 2c (IC50 = 463.85 µM) was more potent antioxidant than quercetin (IC50 = 491.23 µM). Compounds 3b (IC50 = 536.83 µM) and 3c (IC50 = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC50 = 140.02 µM) and 4c (IC50 = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC50 = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC50 = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives’ significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development.

Screening of Polyphenolic compounds to identify dual inhibitors against Glycogen Synthase 3β and Acetylcholinesterase for the treatment of Alzheimer’s Diseases

Alzheimer’s diseases is a neurodegenerative progressive diseases accompanied by complex pathology. Because of its complex pathology, multi-target ligands are considered as an attractive strategy for new drug development against AD. In this context dual inhibition of AChE and GSK-3β can be considered as an important strategy. In this work, various polyphenolic compounds from the literature were collected and evaluated against AChE and GSK-3β using molecular docking. The results indicated good binding potential of all the docked compounds for GSK-3β (9kcal/mol), while weak to good binding potential for AChE (8 to 12kcal/mol). The binding mode analysis of GSK-3 docked complexes showed interactions with key residues like Asp133 and Val135 which are important for molecular recognition. Additionally, the docked compounds showed interactions with Leu132, Arg141 and Cys199, the residues important for potency and selectivity. With respect to AChE, the compounds mostly occupied peripheral aromatic site in the active site of AChE, the site important for binding of ligands and inhibitor. The binding mode analysis showed interactions with key residues Tyr124, Ser293 and Arg296 important for substrate binding and recognition. Further the polar interactions were also noted for His447 and Ser203 (residues important for Ach hydrolysis) in some of the identified ligands. Overall the work resulted in the identification of eight compounds 5'-geranyl-5,7,2',4'tetrahydroxyflavone-2, Kuwanon E 4, Gossypetin, Kaempferide, Galangin, Kaempferol, baicalein and Ellagic acid with the potential dual inhibition of AChE and GSK-3β. It should be noted that kaempferide was not reported in the literature for AChE inhibition, while except baicalein none of the compounds were reported for GSK-3β. Further, the eight identified compounds were subjected for ADME profiling using SwissADME which showed their drug like character. Therefore, based on the results from this study, the above mentioned eight compounds can be looked upon with the potential of dual inhibition against AChE and GSK-3β.

Sulphated Fucooligosaccharide from Sargassum Horneri: Structural Analysis and Anti-Alzheimer Activity.

In the present study, sulfated polysaccharides were obtained by digestion of Sargassum horneri and preparation with enzyme-assisted extraction using three food-grade enzymes, and their anti- Alzheimer's activities were investigated. The results demonstrated that the crude sulfated polysaccharides extracted using AMGSP, CSP and VSP dose-dependently (25-100µg·mL- 1) raised the spontaneous alternating manner (%) in the Y maze experiment of mice and reduced the escape latency time in Morris maze test. AMGSP, CSP and VSP also exhibited good anti-AChE and moderate anti-BuChE activities. CSP displayed the best inhibitory efficacy against AChE. with IC50 values of 9.77 µM. And, CSP also exhibited good inhibitory selectivity of AChE over BuChE. Next, CSP of the best active crude extract was separated by the preparation type high performance liquid phase to obtain the sulphated fucooligosaccharide section: SFcup (→3-α-L-fucp(2-SO3-)-1→4-α-L-fucp(2,3-SO3-)-1→section), SFcup showed a best inhibitory efficacy against AChE with IC50 values of 4.03 µM. The kinetic research showed that SFcup inhibited AChE through dual binding sites. Moreover, the molecular docking of SFcup at the AChE active site was in accordance with the acquired pharmacological results.

Inhibition potential against acetylcholinesterase of commercial and extracts of capsaicin and dihydrocapsaicin by in vitro and in silico studies

The present research investigates the amount of capsaicin and dihydrocapsaicin in three parts of chili extracts (pericarp, seeds, and placenta). Moreover, inhibition potential of capsaicin and dihydrocapsaicin, and chili extracts against AChE were also investigated in vitro and in silico study. The results show that placenta extract had more capsaicin (3818.72 mg/kg DW) and dihydrocapsaicin (2788.37 mg/kg DW) than other extracts. The inhibition potential of dihydrocapsaicin against AChE was higher than that of capsaicin and chili extracts. Which corresponded to the Ki value of dihydrocapsaicin (0.85 mM) higher inhibition potential than that of capsaicin (1.20 mM). The stronger interaction of dihydrocapsaicin than capsaicin at the active site of AChE was also supported by the binding affinity value (−7.8 kcal/mol for dihydrocapsaicin and −7.3 kcal/mol for capsaicin). However, the inhibition modes of dihydrocapsaicin and capsaicin were mixed-type inhibition against AChE. Besides, dihydrocapsaicin and capsaicin were surrounded by aromatic amino acids in the active site of AChE, which caused an increase in fluorescence intensity (FI). A similar increase in FI was also observed in the chili extracts (pericarp, seeds, and placenta). Our results show that capsaicinoids (capsaicin and dihydrocapsaicin) from chili extracts are natural inhibitors of AChE and may be applied to therapeutic Alzheimer's disease.

Aromatic glycosides and lignans glycosides with their acetylcholinesterase inhibitory activities from the leaves of Picrasma quassioides

In this study, eight new natural products were isolated from the leaves of Picrasma quassioides. Spectroscopic techniques were used for the elucidation of their planar structures. Their absolute configurations were elucidated on the basis of electron circular dichroism (ECD) techniques combined with the P/M helicity rule for the 2,3-dihydrobenzofuran chromophore, and saccharide hydrolysis. Cholinesterase inhibitors are often used as Alzheimer's disease inhibitors.Thus, acetylcholinesterase and butyrylcholinesterase inhibitory activity of these eight compounds were tested, and results showed that only compound 6 showed weakly acetylcholinesterase inhibitory activity. In particular, molecular docking was used to illustrate the bindings between compound 6 and the active sites of AChE.

Four Pairs of Neuroprotective Aryldihydronapthalene-type Lignanamide Enantiomers from the Herbs ofSolanum lyratum.

Four pairs of aryldihydronapthalene-type lignanamide enantiomers were isolated from Solanum lyratum (Solanaceae). The enantiomeric separation was accomplished by chiral-phase HPLC, and five undescribed compounds were elucidated. Analysis by various spectroscopy and ECD calculations, the structures of undescribed compounds were illuminated. The neuroprotective effects of all compounds were evaluated using H2O2-induced human neuroblastoma SH-SY5Y cells and AchE inhibition activity. Among them, compound 4a exhibited remarkable neuroprotective effects at high concentrations of 25 and 50 μmol/L comparable to Trolox. Compound 1a showed the highest AchE inhibition with the IC50 value of 3.06 ± 2.40 μmol/L. Molecular docking of the three active compounds was performed and the linkage between the compounds and the active site of AchE was elucidated.

Modeling of a near-attack conformation of oxime in phosphorylated acetylcholinesterase via a reactivation product, a phosphorylated oxime

At the present, only four antidotes are in use in therapy for poisoning by organophosphorus compounds: 2-PAM, HI-6, obidoxime and trimedoxime. Numerous compounds have been designed and synthetized to be more effective reactivators than those currently in use. Many of those new compounds fail at the enzyme level because interactions formed within the AChE active site are not favourable ones that lead to a successful reactivation. The approach in which the modeling of a phosphorylated oxime (POX), a product of successful reactivation in the AChE active site, may be a way to better understand the role of active site residues during the process of formation of the Michaelis type of complex between an enzyme and oxime. After reactivation, a change in phosphorus stereochemistry occurs leading to a different spatial arrangement of attached substituents, now including an oxime. To study interactions between the AChE oxyanion hole and a phosphorylated oxime, an S203G mutant was used to avoid the steric hindrance caused by the catalytic serine. In this way, the POX could be positioned close to the oxyanion hole. In the final step, the oxime without a phosphoester moiety was transferred into the phosphorylated AChE and molecular dynamics was used to test the stability of the near-attack conformation of the oxime near the phosphorylated serine.

Polyphenol-enriched Desmodium elegans DC. ameliorate scopolamine-induced amnesia in animal model of Alzheimer’s disease: In Vitro, In Vivo and In Silico approaches

The current study aims to quantify HPLC-DAD polyphenolics in the crude extracts of Desmodium elegans, evaluating its cholinesterase inhibitory, antioxidant, molecular docking and protective effects against scopolamine-induced amnesia in mice. A total of 16 compounds were identified which include gallic acid (239 mg g-1), p-hydroxybenzoic acid (11.2 mg g-1), coumaric acid (10.0 mg g-1), chlorogenic acid (10.88 mg g-1), caffeic acid (13.9 mg g-1), p-coumaroylhexose (41.2 mg g-1), 3-O-caffeoylquinic acid (22.4 mg g-1), 4-O-caffeoylquinic acid (6.16 mg g-1), (+)-catechin (71.34 mg g-1), (-)-catechin (211.79 mg g-1), quercetin-3-O-glucuronide (17.9 mg g-1), kaempferol-7-O-glucuronide (13.2 mg g-1), kaempferol-7-O-rutinoside (53.67 mg g-1), quercetin-3-rutinoside (12.4 mg g-1), isorhamnetin-7-O-glucuronide (17.6 mg g-1) and isorhamnetin-3-O-rutinoside (15.0 mg g-1). In a DPPH free radical scavenging assay, the chloroform fraction showed the highest antioxidant activity, with an IC50 value of 31.43 µg mL-1. In an AChE inhibitory assay, the methanolic and chloroform fractions showed high inhibitory activities causing 89% and 86.5% inhibitions with IC50 values of 62.34 and 47.32 µg mL-1 respectively. In a BChE inhibition assay, the chloroform fraction exhibited 84.36% inhibition with IC50 values of 45.98 µg mL-1. Furthermore, molecular docking studies revealed that quercetin-3-rutinoside and quercetin-3-O-glucuronide fit perfectly in the active sites of AChE and BChE respectively. Overall, the polyphenols identified exhibited good efficacy, which is likely as a result of the compounds' electron-donating hydroxyl groups (-OH) and electron cloud density. The administration of methanolic extract improved cognitive performance and demonstrated anxiolytic behavior among tested animals.

Synthesis and anti-Alzheimer potential of novel α-amino phosphonate derivatives and probing their molecular interaction mechanism with acetylcholinesterase

Pleiotropic interference may be a prerequisite for the efficient limitation of the progression of multi-factorial diseases such as Alzheimer's disease (AD). Concept of designing the single chemical entity acting on two or more targets of interest has potential advantage in AD therapy. In line with this, rational design and synthesis of frame work of hybrids bearing 2,3-disubstituted quinazolinone, vanillin and α-amino phosphonate scaffolds (5a─v) were carried out. A congeneric set of twenty-two synthetic derivatives (5a─v) were evaluated for their cholinesterase inhibitory, antioxidant, DNA nicking, DNA protection, neuroprotective and Aβ aggregation modulatory activities. Amongst tested activities, the most significant and worth mentioning is that the analogues 5m, 5p and 5u were found to be the most potent, selective, and mixed type inhibitors of EeAChE with IC50 values of 0.296 ± 0.030, 0.289 ± 0.027, and 0.306 ± 0.028 μM, respectively. Further, the biophysical approaches indicated that the compounds 5m, 5p, and 5u have a strong binding affinity towards AChE. Kinetic and Molecular docking studies have revealed that the most active congeners were well oriented in the AChE active site by interacting with both catalytic active site (CAS) and peripheral anionic site (PAS). A few parameters derived from molecular dynamics (MD) simulation trajectories emphasized the stability of AChE-5p and 5m complexes throughout the 100 ns simulations, and the local conformational changes of the residues of AChE validate the stability of AChE-5p and 5m complexes. Further, these derivatives significantly impacted ABTS radical scavenging capacities and maximal DNA protection activity. Importantly, Thioflavin T (ThT) assay and FE-SEM study demonstrated compounds 5m, 5p and 5u as effective Aβ1−42 fibril modulators at molecular level by the formation of micro size co-assembled mature structures, thus efficiently abolishing the cytotoxicity of Aβ1–42. Finally, these active compounds are determined to be non-toxic and highly neuroprotective against H2O2-induced cell death in SK-N-SH cell lines. Furthermore, in silico ADMET prediction studies have revealed that the targeted analogues satisfied most of the characteristics of CNS acting drugs. These multi-functional efficacies indicated worthiness of these α-amino phosphonate derivatives being chosen for further pharmacokinetics, toxicity, and behavioral research to test their potential for AD treatment.

Exploring the potential of Fabiana imbricata Ruiz et Pav. (“Pichi”) against pest insects and pathogenic microorganisms for crop protection

• Fabiana imbricata extracts represents green insecticides for fruit fly control • Scopoletin is the main constituent of Fabiana imbricata active extract • Leaf fractions show repellency activity against Acanthoscelides obtectus adults • The extract has effect on detoxifiying enzimes such as carbolxyl esterases and acetylcholinesterase of Tenebrio molitor . • the components of these fractions could not inhibit the expression of acid and alkaline phosphatase in the intestine of T. molitor The loss of agricultural products by pests and microorganisms is intensely fought with synthetic products that can pose a serious threat to the environment, health, and foods. The use of plant-derived products in the management of these organisms is a sustainable and safe alternative. In this study, we investigated Fabiana imbricata , a very well-known species of Solanaceae found in the Patagonian region. The toxicological effects of its fractions were tested against Drosophila melanogaster and Tenebrio molitor . These fractions were also screened for repellency on Acanthoscelides obtectus and antimicrobial activity. Additionally, the mortality assay of D. melanogaster larvae revealed higher activity for the stem (LC 50 value of 7.5 µg/mL) and leaf (LC 50 value of 19.8 µg/mL) petroleum benzine fractions. T. molitor larvae needed to be exposed to a high concentration of stem fractions (200 and 300 µg/mL) to observe about 50 and 90% mortality, respectively. Moreover, repellency after 4 h of exposure was mainly observed with the stem dichloromethane fraction (conc. 100 µg/mL). The acetate fraction of the stem (FE-C) was responsible for the greatest growth inhibition of the tested bacteria ( E. coli, L. monocytogenes, L. innocua, Salmonella sp., and S. aureus ). Based on the findings, stem fractions were selected for studies of toxicity in non-target organisms and systemic effects on proteins and detoxification enzymes from T. molitor larvae. The fractions tested against adult bees were safe up to 500 µg/mL for 4 h of exposure and 48 h of observation. Total proteins and enzymes AChE, GST/GSH, and Carboxylase were significantly reduced, mainly with FE-C. In contrast, ACP and ALP were up-regulated, with the same fraction as the major inducer. The chemical profiles of the fractions analyzed by GC-MS and NMR showed that FE-C had scopoletin as the main component. Therefore, we selected this compound for in silico analysis of AChE docking, qualitative and quantitative study of insecticide-likeness, and toxicity prediction. The results indicated that scopoletin efficiently docked with the active site of AChE. Due to the high values ​​of Relative Drug Likelihood (RDL) (2.77) and Gaussian Scoring Function (GAU) (4.19) values, ​​it can consider as potential insecticide-likeness and the toxicity prediction study showed that this compound has low toxicity to mammals. These results demonstrate that FE-C has potential as an insecticidal agent against insect pests and can be of help in combating pathogenic microorganisms present in food.

Exploration of a library of piperonylic acid-derived hydrazones possessing variable aryl functionalities as potent dual cholinesterase and monoamine oxidase inhibitors.

A library of piperonylic acid-derived hydrazones possessing variable aryl moiety was synthesized and investigated for their multifunctional properties against cholinesterases (ChEs) and monoamine oxidases (MAOs). The in vitro enzymatic assay results revealed that the tested hydrazones have exhibited excellent cholinesterase inhibition profile. Compound 4i, (E)-N'-(2,3-dichlorobenzylidene)benzo[d][1,3]dioxole-5-carbohydrazide showed promising dual inhibitory profile against AChE (0.048 ± 0.007μM), BChE (0.89 ± 0.018μM), and MAO-B (0.95 ± 0.12μM) enzymes. SAR exploration revealed that the truncation of the linker connecting both the aryl binding sites of the semicarbazone scaffold, by one atom, has relatively suppressed the AChE inhibitory potential. Kinetic studies disclosed that the compound 4i reversibly inhibited AChE enzyme in a competitive manner (Ki = 8.0 ± 0.076nM), while it displayed a non-competitive and reversible inhibition profile against MAO-B (Ki = 9.6 ± 0.021µM). Moreover, molecular docking studies of synthesized compounds against ChEs and MAOs provided the crucial molecular features that enable their close association and interaction with the target enzymes. All atomistic simulation studies confirmed the stable association of compound 4i within the active sites of AChE and MAO-B. In addition, theoretical ADMET prediction studies demonstrated the acceptable pharmacokinetic profile of the dual inhibitors. In summary, the attempted lead simplification study afforded a potent dual ChE-MAO-B inhibitor compound that merits further investigation.

The structure–activity relationship and computational studies of 1,3-thiazole derivatives as cholinesterase inhibitors with anti-inflammatory activity

In our previous research, some screened 1,3-thiazole fragments were found to be potent by inhibiting LPS-induced TNFα and IL-8 release with IC50 values in the μM range without cytotoxic activity. In the current study, 1,3-thiazole fragments were further investigated as potent cholinesterase inhibitors prompted by the previously documented anti-inflammatory effect of AChE inhibitors. Molecular docking enabled insight into stabilizing interactions between the selected thiazoles and the active site of AChE and BChE. According to these experimental results, the cholinesterase inhibitory and anti-inflammatory activity of 1,3-thiazoles were correlated and confirmed that the same compounds inhibited LPS-stimulated TNFα cytokine production in PBMCs and enzymes cholinesterases.

Synthesis of (p‐tolyl)‐3(2H)pyridazinone Derivatives as Novel Acetylcholinesterase Inhibitors

AbstractIn this study, a series of N‐substituted‐(p‐tolyl)pyridazin‐3(2H)‐one derivatives were synthesized and evaluated for their AChE inhibitory activity. The chemical structures of novel compounds 5(a–m) were confirmed by 1H‐NMR, 13C‐NMR, IR and HRMS analysis. In order to eliminate the symptomatic effects of Alzheimer's disease, the proposed compounds were evaluated by acetylcholinesterase inhibition activity study in accordance with the cholinergic hypothesis. The results revealed that the N‐substituted‐(p‐tolyl)pyridazin‐3(2H)‐one derivatives inhibited the enzymes significantly. Ki values for acetylcholinesterase in the range of 0.56±0.15–4.12±1.42 μM. Compound 5 h demonstrated the greatest in AChE activity compared with tacrine (0.56±0.15 μM). Molecular docking studies were performed for all compounds that compared tacrine in AChE activity in‐vitro. As a result of molecular docking studies (ΔGBind, docking score, XP Gscore, Glide energy, Glide emodel), 5 f, 5 g and 5 h compounds showed good inhibitory properties in the AChE active site as in silico.

Effect of chlorogenic acid plus donepezil on critical neurocortical enzyme activities, inflammatory markers, and synaptophysin immunoreactivity in scopolamine-assaulted rats, supported by multiple ligand simultaneous docking.

The effect of chlorogenic acid (a natural phenolic acid ubiquitous in plant foods) on selected therapeutic properties of donepezil (DON) in a scopolamine (SCOP)-induced rat model of amnesia was the focus of this study. Adult albino (Wister strain) rats were allocated into five groups (n=11) consisting of control, SCOP, SCOP + chlorogenic acid (CGA), SCOP + DON, and SCOP + CGA + DON for 7 days. Post-treatment, the rat brain cerebral cortex homogenate was assayed for cholinesterase and monoamine oxidase activities. Also, the reactive oxygen species, total thiol and nitric oxide contents, alongside catalase, and superoxide dismutase activities were determined. Routine histology for neuronal and glial cells as well as synaptophysin immunoreactivity was also carried out on the cerebral cortex. Thereafter, multiple ligand simultaneous docking was carried out for DON and CGA at the active sites of AChE and BChE. The results revealed that the biochemical parameters, glial cells, and synaptophysin immunoreactivity were significantly impaired in the cerebral cortex of scopolamine-treated rats. However, impaired butyrylcholinesterase and monoamine oxidase activity, together with antioxidant, glial cells, and synaptophysin levels were significantly ameliorated in scopolamine-treated rats administered DON + CGA compared to donepezil alone. The docking of both DON and CGA at the active sites of AChE or BChE showed higher binding energy to both enzymes compared to individual interactions of either DON or CGA. Hence, this study has been able to show that CGA could improve some of the therapeutic effects of DON, which could broaden the therapeutic spectrum of this drug. PRACTICAL APPLICATIONS: This study showed that chlorogenic acid (a major phenolic acid found in plant foods such as coffee) modulated some of the therapeutic properties of donepezil (an anticholinesterase drug used in the treatment of mild-to-moderate Alzheimer's disease). The combinations elicited better anti-butyrylcholinesterase, antimonoamine oxidase, and antioxidant properties, thus presenting this food-drug interaction as potentially able to offer better therapeutic properties.

Docking and 2D-Structure-activity Relationship and ADMET Studies of Acetylcholinesterase Inhibitors

In this work, a quantitative structure-activity relationship (QSAR) for some tacrine derivatives inhibitors of acetylcholinesterase was modeled using ligand-receptor interconnection interaction space. The descriptors were obtained by multivariate image analysis (MIA) of each molecule. Docking studies were performed to determine the best conformers of inhibitors. In the first step, the best pose of all the ligands was selected. Afterward, an MIA-QSAR model using ligand-receptor interconnection data was developed. The pool of descriptors was compressed by principal component analysis (PCA). Variable selection was carried out by genetic algorithm (GA) followed by model building using the support vector machine (SVM) regression method. The validation of the model's predictive ability was studied by a validation set containing 11 individual compounds. The Q2, r2 and, ∆r_m^2 test prediction values for PCA-GA-SVM model were 0.62, 0.89 and 0.145, respectively. After validating the results with all statistical data, three new molecules were designed by the MIA-QSAR model. Afterward, new molecules docked in the AChE active site. Docking studies were showed the amino acids TYR70, TYR121, TYR334, TRP279, PHE288, PHE290, TRP84, TRP334, and SER286 are active amino acids in the complex. Finally, the ADMET parameters of the new compounds were calculated and were in acceptable ranges.

Synthesis, photochemistry and computational study of novel 1,2,3-triazole heterostilbenes: Expressed biological activity of their electrocyclization photoproducts

New 1,2,3-triazolostilbenes were synthesized and photochemically transformed to substituted naphthotriazoles as electrocyclization products in high isolated yields for studying the acetyl- and butyrylcholinesterase inhibitory and anti-inflammatory activity. The best experimental results showed the naphthotriazole photoproducts providing interesting observation on cholinesterase inhibition associated with the inhibition of TNFα cytokine production. The geometries of synthesized triazolostilbenes were computationally examined using Density Functional Theory (DFT), followed by time-dependent DFT calculations to obtain insight into electronic properties observed by UV–Vis spectroscopy. The complexes between selected compounds with the active site of AChE are assessed by docking. A quantum mechanical cluster approach was utilized to optimize their structures, thus providing insight into the stabilizing interactions between the potential inhibitor and the active site.

Integration of System Biology Tools to Investigate Huperzine A as an Anti-Alzheimer Agent.

Aim: The present study aimed to investigate huperzine A as an anti-Alzheimer agent based on the principle that a single compound can regulate multiple proteins and associated pathways, using system biology tools. Methodology: The simplified molecular-input line-entry system of huperzine A was retrieved from the PubChem database, and its targets were predicted using SwissTargetPrediction. These targets were matched with the proteins deposited in DisGeNET for Alzheimer disease and enriched in STRING to identify the probably regulated pathways, cellular components, biological processes, and molecular function. Furthermore, huperzine A was docked against acetylcholinesterase using AutoDock Vina, and simulations were performed with the Gromacs package to take into account the dynamics of the system and its effect on the stability and function of the ligands. Results: A total of 100 targets were predicted to be targeted by huperzine A, of which 42 were regulated at a minimum probability of 0.05. Similarly, 101 Kyoto Encyclopedia of Genes and Genomes pathways were triggered, in which neuroactive ligand–receptor interactions scored the least false discovery rate. Also, huperzine A was predicted to modulate 54 cellular components, 120 molecular functions, and 873 biological processes. Furthermore, huperzine A possessed a binding affinity of −8.7 kcal/mol with AChE and interacted within the active site of AChE via H-bonds and hydrophobic interactions.

New benzimidazolium N-heterocyclic carbene precursors and their related Pd-NHC complex PEPPSI-type: Synthesis, structures, DFT calculations, biological activity, docking study, and catalytic application in the direct arylation

New benzhydryl-5,6-dimethyl-(3-methylbenzyl)benzimidazolium salt as N-heterocyclic carbene precursors and their related new Pd-NHC complex PEPPSI-type with the general formula [PdBr2(NHC)(pyridine)] were prepared and theoretically studied. Quantum chemistry computations at the B3LYP/6-311G(d,p)/LANL2DZ level were used to examine the molecular structure, electronic characteristics, and chemical reactivity of the ligand and its Pd complex. Further, the structural characterization of the complex (c) was determined by a single-crystal X-ray diffraction study, which supports the proposed structures and offered a more detailed structural characterization. In addition, their biological activity against.cholinesterase enzymes were also determined. The new compounds were tested against two enzymes (AChE and BChE), furthermore, docking studies were carried out in order to gain a better understanding of the bonding modes of L and COP in the active sites of AChE and BChE enzymes. The new salt and Pd-NHC complex PEPPSI-type were fully characterized by spectroscopic and analytical methods. The new Pd-catalysts based N-heterocyclic carbene ligand PEPPSI-Type was applied by the direct arylation process of five-membered heteroaromatics such as thiophene, and furan derivatives with various (hetero)aryl bromides in the presence of 1 mol% catalyst, using KOAc as a co-catalyst. The results showed that the new Pd-NHC complex is an effective catalyst.