Cholinesterase Research Articles

A Series of Biguanide Ligands and Their Cu(II) Complexes: Cholinesterase Inhibitory and Antimicrobial Properties.

In this work, a series of biguanide hydrochloride salts and their Cu(II) complexes were synthesized and screened for their acetyl/butyryl choline esterase inhibitory and antimicrobial properties. The structures of the synthesized compounds were characterised by common spectroscopic and analytical methods. Biguanide compounds showed considerably lower inhibitory activity compared to the reference drugs donepezil and galantamine. On the other hand, complexation of the biguanide compounds with Cu(II) resulted in dramatic increase in the inhibitory activity. The Cu(II) complexes showed AChE inhibitory activity with the IC50 values of 21.29±0.95-82.53±0.20 μM and those values are comparable to that of donepezil (IC50 : 18.54±1.03 μM). The synthesised compounds were also screened for their antimicrobial activity towards gram positive (+) and gram negative (-) bacteria. Compounds (12.50 mg/mL) showed important antibacterial properties with inhibition zones of 8-28 mm diameter against gram-positive and gram-negative microorganisms. Compounds A03 and A08 exhibited more antimicrobial properties towards E. coli than standard antibiotics amikacin and gentamicin.

Adverse neurobehavioral changes with reduced blood and brain cholinesterase activities in mice treated with statins.

Pleiotropic effects of hypolipidemic statins with behavioral outcomes have been suggested in humans and laboratory animals. There is limited information on the neurobehavioral effects of statins in mice. The aim of the present study was to examine changes in neurobehavioral performance and cholinesterase (ChE) activity in mice after high doses of three commonly used statins (atorvastatin, simvastatin, and rosuvastatin). Two hours after vehicle (control) or statin dosing at 250, 500, 750, or 1000 mg/kg orally, each mouse was subjected to 5 min open-field activity, negative geotaxis at an angle of 45°/60 s, 5 min head pocking, and forced swimming endurance. Plasma, erythrocyte, and brain ChE activities were determined spectrophotometrically 2 and 24 h after oral dosing of statins at 500 and 1000 mg/kg. The statins variably, but dose-dependently and significantly (p < 0.05) delayed the latency to move in the open-field arena, decreased locomotion and rearing, reduced head pocking, and delayed negative geotaxis performance. However, statins significantly increased the duration of forced swimming and decreased the duration of immobility in the swimming tank. Statins significantly and dose-dependently decreased plasma, erythrocyte, and brain ChE activity 2 and 24 h after dosing. Plasma and brain ChE activities recovered by 5%-32.9% and 5.7%-14.4% 24 h later from the 2 h ChE values, respectively. High doses of statins differentially modulate neurobehavioral outcomes in mice in association with reduced plasma, erythrocyte, and brain ChE activity. Plasma or erythrocyte ChE may be used for biomonitoring of the adverse/therapeutic effects of statins.

The therapeutic value of thiazole and thiazolidine derivatives in Alzheimer's disease: a systematic literature review.

Alzheimer's disease (AD) is a common neurodegenerative disease and the fifth leading cause of death among the elderly. The development of drugs for AD treatment is based on inhibiting cholinesterase (ChE) activity and inhibiting amyloid-beta peptide and tau protein aggregations. Many in vitro findings have demonstrated that thiazole-and thiazolidine-based compounds have a good inhibitory effect on ChE and other elements involved in the AD pathogenicity cascade. In the present review, we collected available documents to verify whether these synthetic compounds can be a step forward in developing new medications for AD. A systematic literature search was performed in major electronic databases in April 2021. Twenty-eight relevant in vitro and in vivo studies were found and used for data extraction. Findings demonstrated that thiazole-and thiazolidine-based compounds could ameliorate AD's pathologic condition by affecting various targets, including inhibition of ChE activity, amyloid-beta, and tau aggregation in addition to cyclin-dependent kinase 5/p25, beta-secretase-1, cyclooxygenase, and glycogen synthase kinase-3β. Due to multitarget effects at micromolar concentration, this review demonstrated that these synthetic compounds could be considered promising candidates for developing anti-Alzheimer drugs.

Quinoline-sulfonamides as a multi-targeting neurotherapeutic for cognitive decline: in vitro, in silico studies and ADME evaluation of monoamine oxidases and cholinesterases inhibitors.

Alzheimer's disease (AD) is a multifactorial irreversible neurological disorder with multiple enzymes involved. In the treatment of AD, multifunctional agents targeting cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have shown promising results. Herein, a series of novel quinoline-sulfonamides (a1-18) were designed and synthesized as a dual inhibitor of MAOs and ChEs. The in vitro results showed that compounds a5, a12, a11, and a6 exhibited the most potent compounds against specific enzymes. They had IC50 value 0.59 ± 0.04 for MAO-A, 0.47 ± 0.03 for MAO-B, 0.58 ± 0.05 for BChE and 1.10 ± 0.77 for AChE μM respectively. Furthermore, kinetic studies revealed that these compounds are competitive. Molecular docking studies enhanced the understanding of the in silico component, unveiling critical interactions, specifically the hydrogen bonding interaction, π-π, π-alkyl, π-amid and π-sulfur interactions between the ligand and enzymes. These findings suggest that compounds a5, a6, a11, a12, a15, and a18 may be potent multifunctional candidates for AD treatment.

Synthesis of 2,8-Dioxabicyclo[3.3.1]nonane Derivatives and Their Neuroprotective Activities.

Twenty natural-product-like 2,8-dioxabicyclo[3.3.1]nonane derivatives were synthesized and their neuroprotective activities were tested using human monoamine oxidases (MAO) A and B and acetyl and butyryl cholinesterases (ChE). Compound 1s showed inhibitory activity for MAO-A, MAO-B and acetylcholinesterase (AChE) (IC50 values 34.0, 2.3 and 11.0 µM, respectively). The inhibition mode of (-)-1s for MAO-B was investigated. Chiral HPLC of (±)-1s separated the enantiomers and (-)-1s showed MAO-B inhibitory activity. Molecular docking simulation of (-)-1s and MAO-B revealed the binding mode.

Design, Synthesis and Biological Activity Studies of 2-(1,3-Dioxoiso-indolin-2-yl)-N-phenethylacetamide and 2-(3,4-Dihydroisoquinolin-1-yl)isoindole-1,3-dione as Monoamine Oxidase (MAO) and Cholinesterase (ChE) Inhibitors

Design, Synthesis and Biological Activity Studies of 2-(1,3-Dioxoiso-indolin-2-yl)-N-phenethylacetamide and 2-(3,4-Dihydroisoquinolin-1-yl)isoindole-1,3-dione as Monoamine Oxidase (MAO) and Cholinesterase (ChE) Inhibitors

Identification of coumarin derivatives targeting acetylcholinesterase for Alzheimer's disease by field-based 3D-QSAR, pharmacophore model-based virtual screening, molecular docking, MM/GBSA, ADME and MD Simulation study

Alzheimer's disease (AD) leads to gradual memory loss including other compromised cognitive abilities. Acetylcholinesterase (AChE), an important biochemical enzyme from the cholinesterase (ChE) family, is recognized as primary pharmacological target for treating AD. Currently marketed drugs for AD treatment are primarily AChE inhibitors and coumarin derivatives comprising a wide variety of pharmacological activities have proved their efficacy towards AChE inhibition. Ensaculin (KA-672 HCl), a compound that belong to the coumarin family, is a clinical trial candidate for AD treatment. Therefore, a ligand library was prepared with 60 reported coumarin derivatives for field-based 3D-QSAR and pharmacophore modelling. The field-based 3D-QSAR model obtained at partial least square (PLS) factor 7, was the best validated model that predicted activity closer to original activity for each ligand introduced. The contour maps demonstrated spatial distribution of favourable and unfavorable steric, hydrophobic, electrostatic and H-bond donor and acceptor contours around coumarin nucleus. The best pharmacophore model, ADHRR_1 exhibited five essential pharmacophoric features of four different traits for optimum AChE inhibition. Virtual screening through ADHRR_1 accompanied with molecular docking and MM/GBSA identified 10 HITs from a 4,00,000 coumarin derivatives from PubChem database. HITs comprised docking scores ranging from −12.096 kcal/mol to −8.271 kcal/mol and compared with the reference drug Donepezil (-8.271 kcal/mol). ADME properties analysis led into detecting two leads (HIT 1 and HIT 2) among these 10 HITs. Molecular Dynamics Simulation indicated thermodynamic stability of the complex of lead compounds with AChE protein. Finally, thorough survey of the experimental results from 3D-QSAR modelling, pharmacophore modelling and molecular docking interactions led us to develop the lead formula I for future advancements in treating AD through AChE inhibitors.

Synthesis and evaluation of a highly selective cannabidiol amide cholinesterase inhibitor

The therapeutic mechanism for the treatment of Alzheimer's disease (AD) is mainly by inhibiting the activity of cholinesterase (ChE) and increasing the transmission of choline and the function of neurons. In this study, two series of ChE inhibitors (CA1–CA8 and CB1–CB7) were designed and synthesized by the acylation of a cannabinoid (CBD) with bromoacetyl bromide, or the esterification of a CBD with an amino acid. All the synthesized compounds were tested for in vitro activity to evaluate the compounds as AD therapies. Compound CB7 was identified as a potential butyrylcholinesterase (BuChE) inhibitor (IC50 = 0.31 ± 0.09 μM), which did not display toxicity against HepG2 or PC12 cells at 6.25 μM. Compound CB7 showed good antioxidant behavior, effective anti-tyrosinase activity (IC50 = 0.037 ± 0.003 μM), and anti-acetylcholinesterase (AChE) activity (IC50 = 19.73 ± 0.79 μM). Kinetic studies also showed that CB7 can act as a dual inhibitor. These results provide a theoretical basis for the use of the natural product CBD in the design and development of anti-AD drugs.

Blood cholinesterase enzyme activity profile of fogging officers at the Makassar health quarantine centre

Blood cholinesterase enzyme activity profile of fogging officers at the Makassar health quarantine centre

Some biological parameters and cholinesterase enzyme profile of Tilapia sp. along Maragondon River, Cavite, Philippines

Some biological parameters and cholinesterase enzyme profile of Tilapia sp. along Maragondon River, Cavite, Philippines

The correlation between serum creatinine and burn severity and its predictive value.

This study aimed to explore the correlation between serum creatinine and burn severity and the value of predicting the outcome of patients. For this purpose, a total of 268 burn patients (BUP) were collected. According to the burn area, they were divided into mild group (MIG) (n = 125, burn area 30% - 49%), moderate group (MOG) (n = 80, burn area 50% - 79%) and severe group (SEG) (n = 63, burn area ≥ 80%). According to the prognosis, they were divided into survival group (SUG) (n = 170) and death group (DEG) (n = 98). At the same time, the control group (COG) was selected from the physical examination center of our hospital. 5 mL of fasting venous blood was collected from all BUP on the first, seventh, 14th and 21st days after admission. 5 mL of fasting venous blood was collected from the COG. Creatinine (CRE) level was measured by enzyme method. Cholinesterase (CHE) level in serum was measured by improved Ellman method. The changes of CRE and CHE in serum were compared among all groups to explore the correlation between serum creatinine and burn severity and its prediction Measure the value of patients' outcomes. Results showed that except for the first day after burn, the level of serum CRE in BUP was raised than that in the COG, and the level of serum CHE in BUP was reduced than that in the COG (P<0.05). The serum CHE level of BUP in all groups increased at first and then decreased, and the highest level was on the first day after injury. At the same time, the level of CRE in SEG was raised than that in MIG and MOG, and the level of CRE in MOG was raised than that in MIG (P<0.05). The serum CHE level of BUP in all groups decreased at first and then increased, and the lowest level was on the first day after injury. At the same time, the level of CRE in SEG was reduced to that in MIG and MOG, and the level of CRE in MOG was reduced to that in MIG (P<0.05). The level of CRE in serum of BUP in both groups increased at first and then decreased, and the level was the highest on the first day after injury. At the same time, the level of CRE in the DEG was raised than that in the SUG (P<0.05). The level of CHE in serum of BUP in both groups decreased at first and then increased, and the level was the lowest on the first day after injury. At the same time, the level of CRE in the death group was reduced than that in the SUG (P<0.05). Logistic regression analysis showed that there was statistical significance in the regression coefficients on the 1st, 7th, 14th and 21st day after burn, and on the 1st and 21st day after-burn. ROC curve analysis shows that CRE and CHE have certain value in diagnosing the prognosis of BUP, and the diagnostic value of CRE is higher. Cre level increases with the aggravation of burn patients, and ChE level decreases with the aggravation of BUP. In conclusion, Cre and ChE have certain value in diagnosing the prognosis of BUP and can be widely used in clinical practice.

Theoretical insights into the HO●-induced oxidation of chlorpyrifos pesticide: Mechanism, kinetics, ecotoxicity, and cholinesterase inhibition of degradants

The oxidation of the common pesticide chlorpyrifos (CPF) initiated by HO● radical and the risks of its degradation products were studied in the gaseous and aqueous phases via computational approaches. Oxidation mechanisms were investigated, including H-, Cl-, CH3- abstraction, HO●-addition, and single electron transfer. In both phases, HO●-addition at the C of the pyridyl ring is the most energetically favorable and spontaneous reaction, followed by H-abstraction reactions at methylene groups (i.e., at H19/H21 in the gas phase and H22/H28 in water). In contrast, other abstractions and electron transfer reactions are unfavorable. However, regarding the kinetics, the significant contribution to the oxidation of CPF is made from H-abstraction channels, mostly at the hydrogens of the methylene groups. CPF can be decomposed in a short time (5–8 h) in the gas phase, and it is more persistent in natural water with a lifetime between 24 days and 66 years, depending on the temperature and HO● concentration. Subsequent oxidation of the essential radical products with other oxidizing reagents, i.e., HO●, NO2●, NO●, and 3O2, gave primary neutral products P1–P15. Acute and chronic toxicity calculations estimate very toxic levels for CPF and two degradation products, P7w and P12w, in aquatic systems. The neurotoxicity of these products was investigated by docking and molecular dynamics. P7w and P12w show the most significant binding scores with acetylcholinesterases, while P8w and P13w are with butyrylcholinesterase enzyme. Finally, molecular dynamics illustrate stable interactions between CPF degradants and cholinesterase enzyme over a 100 ns time frame and determine P7w as the riskiest degradant to the neural developmental system.

Biochemical, Toxicological, and in Silico Aspects of Trillium govanianum Wall. ex D.Don (Trilliaceae): A Rich Source of Natural Bioactive Compounds.

Trillium govanianum is a high-value medicinal herb, having multifunctional traditional and culinary uses. The present investigation was carried out to evaluate the phytochemical, biological and toxicological parameters of the T. govanianum Wall. ex D. Don (Family: Trilliaceae) roots collected from Azad Kashmir, Pakistan. Phytochemical profiling was achieved by determining total bioactive contents (total phenolic and flavonoid contents) and UHPLC-MS analysis. For biological evaluation, antioxidant activities (DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum, and metal chelation assays) and enzyme inhibition activities (against AChE, BChE, glucosidase, amylase, and tyrosinase) were performed. Moreover, cytotoxicity was assessed against three human carcinoma cell lines (MDA-MB-231, CaSki, and DU-145). The tested extract was found to contain higher total phenolics (7.56 mg GAE/g dry extract) as compared to flavonoid contents (0.45 mg RE/g dry extract). Likewise, for the antioxidant activity, higher CUPRAC activity was noted with 39.84 mg TE/g dry extract values. In the case of enzyme assays, higher activity was pointed out against the cholinesterase, glucosidase and tyrosinase enzymes. The plant extract displayed significant cytotoxicity against the cell lines examined. Moreover, the in-silico studies highlighted the interaction between the important phytochemicals and tested enzymes. To conclude, the assessed biological activity and the existence of bioactive phytochemicals in the studied plant extract may pave the way for the development of novel pharmaceuticals.

Effects of fenobucarb based-Excel Basa 50EC on brain cholinesterase of juvenile snakehead fish (Channa striata) in the Vietnamese Mekong Delta's rice fields.

Fenobucarb is one of most common insecticides applied to rice crops in the Vietnamese Mekong Delta. Paddy fields are preferred habitats for snakehead fish (Channa striata). Therefore, the probability of exposure risks and growth effects is highly. This paper aimed to examine the effects of using fenobucarb based - Excel Basa 50EC on the brain cholinesterase (ChE) of snakehead fish. Two rice fields, in which a single dose of Excel Basa 50EC was applied to one field, whilst the other acted as a control. Each field was subdivided into three plots by earthen dikes. In each plot, one fish cage (1.2 m x 1.2 m x 1.2 m) was installed that was stocked with 20 snakehead fish. The Excel Basa 50EC was applied once at the indication dose. The results highlighted that the concentration of fenobucarb in water at 1 hr after application was 116.72 ppb ± 12.64, which decreased to 23.96 ± 6.61 ppb after d and then to below detection limits (0.02 ppb). For fish living in this field, no mortality was seen, but ChE was significantly inhibited for 31 % on the first day and recovery following 7 days of exposure. Residues of fenobucarb in soil and fish should also be investigated furthermore.

Plasma Cholinesterase Activity in Patients With Rheumatoid Arthritis and Toxoplasmosis.

Background and objective Rheumatoid arthritis (RA) is a chronic autoimmune disease causing synovium inflammation and functional impairment. Toxoplasmosis is an intracellular zoonotic parasitic infection anda risk factor in immunosuppressed diseases including RA. The involvement of the cholinergic mechanism is not clear when both diseases exist in combination. This study aimed to examine plasma cholinesterase (ChE) activity in patients suffering from RA with concomitant toxoplasmosis, taking into account the enzyme susceptibility to in vitro inhibitory challenge with the organophosphate dichlorvos in RA patients. Methods This was a case-control study involving 88 RA patients and 61 healthy controls of both genders.The RA patients were allocated into three groups. The first group received no therapy (n=14), the second group received conventional anti-arthritis therapy (n=49), and the third group received conventional+biologic therapy(n=25). Plasma ChE activity was determined by an electrometric method. Plasma samples were screened for Toxoplasmagondii (T. gondii)infection, using ELISAT. gondii antibodies IgG andIgM.In vitro inhibition of plasma ChE activitywas assessed by incubating the samples with dichlorvos at0.25 and 0.5 μM.The time-dependent dichlorvos (0.25 μM)-induced plasma ChE inhibition and its kinetics weredetermined. Results The RA patients comprised 76 (86.4%) females and 12 males (13.6%), whereas healthy controls included 22 (36.1%) females and 39 (63.9%) males. The rates of toxoplasmosis IgG positivity in controls and RA patients were 26.2% and 39.8%, respectively. Plasma ChE activity in patients with RA was significantly higher than that in the control group, by 16%. Plasma ChE values of RA patients with conventional therapy and conventional + biologic therapy were higher than that of the control group, by 18% and 27%, respectively. Odds and risk ratios of elevated plasma ChE activity (20%) in RA patients with therapyindicated that high plasma ChE activity among RA patients with therapyis a risk factor. The plasma ChE activity of T. gondii IgG-positive RA patients was not significantly different from that of theIgG-negative ones. Dichlorvos at 0.25 and 0.5 μM significantly inhibited in vitro plasma ChE activity incontrols and RA patients. The rates of plasma ChE inhibition by dichlorvos were lower in the RA groups with conventional therapyin comparison with those in the control group (77% vs. 91%). Examining the dichlorvos time-dependent ChE inhibition kinetics, RA groups showed increases in the half-life of inhibition by 23.6% to 32.7% and the total inhibition time by 23.5% to 32.5%, together with decreases in the inhibition rate constant by 19% to 24.5%, an indication of reduced inhibition rate of plasma ChE activity compared to that of the control group. Conclusions The autoimmune nature of RA and its chronicity might have contributed to the increase in plasma ChE activity among the patients. This increase in enzyme activity could be a risk factor in RA patients undergoing conventional therapy alone or in combination with biologic therapy; however, the clinical significance of such a condition remains obscure at present. The in vitro inhibition of plasma ChE activity in RA patients suggests reduced susceptibility of the enzyme to ChE inhibition by dichlorvos. Toxoplasmosis was not a risk factor when plasma ChE activity was taken into account among RA patients.

Exploring the Pharmacological Potential of Onosma riedliana: Phenolic Compounds and Their Biological Activities

Onosma riedliana Binzet & Orcan, a traditionally used plant species, has been explored for its therapeutic potential in this study. The work presented here is the first report on the phenolic profile and biological activity of this species. Three extracts of varying polarity were prepared, with the methanolic extract containing the highest phenolic content (97.62 ± 0.20 mgGAE/g). Key phenolic compounds identified included pinoresinol, hesperidin, 4-hydroxybenzoic acid, and p-coumaric acid. The methanolic extract exhibited exceptional antioxidant properties, rivaling Trolox as a positive control, primarily attributed to hesperidin and luteolin. Moreover, the ethyl acetate extract demonstrated remarkable inhibition of cholinesterase and tyrosinase enzymes, while the methanolic extract displayed potent activity against carbohydrate hydrolytic enzymes, α-amylase and α-glucosidase. Again, phenolic compounds were shown to be responsible for the inhibition of cholinesterases and tyrosinase, but not for α-amylase and α-glucosidase. These findings underscore Onosma riedliana’s potential for incorporation into diverse pharmaceutical formulations, given its multifaceted bioactivity.

Bioactive sulfonyl hydrazones with indole scaffold, characterization, adme properties, molecular docking studies and investigation of inhibition on choline esterase enzymes for the diagnosis of Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is a progressive and neurodegenerative disease that is primarily seen in the elderly population and is clinically characterized by memory and cognitive impairment. This study aimed to find new ChE inhibitors.MethodThe structures of the synthesized compounds were characterized by 1H NMR, 13C NMR and HRMS. The effects of the synthesized hydrazones on acetylcholinesterase and butyrylcholinesterase enzymes were measured using the microplate assay described in the Ellman test, with modifications added by López (2002).ResultAccording to the results, all the synthesized compounds inhibited AChE and BChE enzymes. When the IC50 values were compared, the compounds with indole scaffold and donepezil fragment showed potent inhibitory activity on the AChE enzyme. In addition, the predictive properties of all compounds in terms of drug similarity were scanned using five Lipinski rules and ADME. Also, to evaluate the binding interactions between the hydrazone compounds and enzymes, molecular docking studies were performed and the compounds with the best inhibition effect were tested. Promisingly, the compound 3d showed good permeability in the PAMPA‐BBB model and high in vitro antioxidant activity.ConclusionBoth in vitro and in silico results showed that two compounds could act as promising inhibitors of AChE and the data provided the way to guide future studies.FundingThis research was funded by the Bulgarian National Science Fund (Grant KP‐06‐Н63/11 14.12.2022).

Back‐translation of clinical tau‐aggregation inhibitor trials to experimental models: negative interactions of dementia therapies

AbstractBackgroundAlzheimer disease (AD) has attracted considerable interest in novel therapies. Two Phase III trials by TauRx Pharmaceuticals (TRx‐005, TRx‐015) failed to attain their endpoints. A significant number of recruits, however, remained on symptomatic treatment and a post‐hoc analysis confirmed this sub‐cohort was selectively resilient against the tau aggregation inhibitor hydromethylthionine (HMT; previously termed LMT). By contrast, drug‐naïve patients were highly sensitive to the novel therapy and showed little decline over 18‐month. We here back‐translated this study to the preclinic.MethodsExperiments used female tau transgenic Line 1 mice (L1) aged 6‐8 months previously characterised for cognitive impairments, tau pathology, and sensitivity to the tau aggregation inhibitor HMT. Here, multiple groups and doses of drugs were chronically administered (up to 11 weeks) with pre‐exposure to the acetylcholine esterase inhibitor rivastigmine followed by add‐on of HMT. Drugs were also dosed singly.Results(i) Tested for spatial learning in the water maze, L1 mice were significantly impaired and benefitted from exposure to HMT. By contrast, combination therapy with rivastigmine precluded some of the benefits of HMT while rivastigmine alone was non‐efficacious.(ii) Chronic drug administration was followed by tissue harvest and histological preparation of sections through 6 brain regions (3 x cortical, 3x basal forebrain) and labelling of 6 presynaptic structural (3) and functional proteins (3. Reduced protein levels were found in cortex; they were heightened by HMT, but abnormally altered in the presence of rivastigmine (single and combination therapy).(iii) Chronic drug administration was followed by in vivo brain dialysis from hippocampus for acetylcholine at rest and under behavioural challenge. L1 showed a lowering of cholinergic neurones in the basal forebrain, but no difference in acetylcholine levels at rest; a heightening of choline levels was observed to HMT alone at rest and challenge, but not to combinations with rivastigmine.ConclusionWe successfully back‐translate the clinical trials on HMT into the preclinic using L1 tau transgenic mice . Data suggest not only a reduced cognitive efficacy of HMT in subjects pre‐exposed to the choline esterase inhibitor rivastigmine, but also offer mechanistic explanations for potential interactions at presynaptic function and for transmitter release.

New resveratrol analogs as improved biologically active structures: Design, synthesis and computational modeling

New analogs of the well-known bioactive trihydroxy-stilbene resveratrol were synthesized to investigate their potential biological activity. The focus was on assessing their ability to inhibit cholinesterase enzymes (ChEs) and their antioxidative properties, which were thoroughly examined. New resveratrol analogs were synthesized through Wittig or McMurry reaction in moderate-to-good yields. In all synthetic pathways, mixtures of cis- and trans-isomers were obtained, then separated by chromatography, and trans-isomers were isolated as targeted structures. The stilbene derivatives underwent evaluation for antioxidant activity (AOA) using DPPH and CUPRAC assay, and their potential to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) was also measured. The biological tests have shown that the same compounds exhibited significant antioxidative and butyrylcholinesterase inhibitory potential, as evidenced by lower IC50 values compared to the established standards, trans-resveratrol, and galantamine, respectively. Additionally, molecular docking of the selected synthesized potential inhibitors to the enzyme's active site was performed, followed by assessing the complex stability using molecular dynamics simulation lasting 100 ns. Lastly, the new compounds underwent examination to determine their potential mutagenicity.

Design, synthesis, and biological evaluation of novel tryptanthrin derivatives as selective acetylcholinesterase inhibitors for the treatment of Alzheimer's disease

Two novel series of tryptanthrin (TRYP) derivatives were designed and synthesized as multifunctional agents for the treatment of Alzheimer’s disease (AD). Inhibition assay against cholinesterase (ChE) indicated that these derivatives can act as acetylcholinesterase (AChE) inhibitors with selectivity over butyrylcholinesterase (BuChE). Among them, n1 exhibited the most excellent ChE inhibitory potency (AChE, IC50 = 12.17 ± 1.50 nM; BuChE, IC50 = 6.29 ± 0.48 μΜ; selectivity index = 517). Molecular docking studies indicated that compound n1 can interact with amino acid residues in the catalytic active site and peripheral anionic site of AChE and the molecular dynamics (MD) simulation studies demonstrated that the AChE–n1 complex had good stability. N1 also exhibited anti-amyloid-β (Aβ) aggregation (63.48 % ± 1.02 %, 100 μΜ) and anti-neuroinflammation activity (NO, IL-1β, TNF-α; IC50 = 2.13 ± 0.54 μΜ, 2.21 ± 0.37 μΜ, 2.47 ± 0.07 μΜ, respectively), and n1 had neuroprotective and metal-chelating properties. Further studies indicated n1 had proper blood–brain barrier permeability in the Parallel artificial membrane permeation assay. In vivo studies found that n1 effectively improved learning and memory impairment in scopolamine-induced AD mouse models. Nissl staining ofmice hippocampaltissue sections revealed that n1 restored neuronal cells in the hippocampus CA3 and CA1 regions. These findings suggested that n1 can be a promising compound for further development of multifunctional agents for AD treatment.