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2,3-disubstituted acrylonitriles derivatives are among the most important molecules in medicinal chemistry due to their bioactivity and their role as starting compounds for many bioactive molecules. Many heterocyclic structures have been investigated as AChE enzyme inhibitors. Nowadays, E/Z acrylonitrile derivatives are being studied as new AChE inhibitors. This study aimed to synthesis new heteroaryl-acrylonitrile compounds using Knoevenagel condensation. In this context, acrylonitrile compounds with aryl and heteroaryl structures at positions 2 and 3 (respectively )were synthesized from the reactions of pyrazole aldehyde derivative (4) with various acetonitrile compounds. Synthesized novel heteroarylacrylonitrile derivatives (5a-d) containing pyrazole ring are potential AChE inhibitors. The structures of the synthesized compounds were elucidated by FTIR, ¹H-NMR and 13C-NMR spectroscopic techniques. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a destructive neurological disease. Approved therapies that target the cholinergic system to control the symptoms have various complications. Natural compounds that inhibit the acetylcholinesterase (AChE) enzyme can promote the development of new drugs. Nature‐derived compounds are more compatible with biological systems in comparison to synthetic library. Ferula haussknechtii is a native species of Iran. In study, we evaluated the effects of its essential oil and extracts on the inhibition of AChE through in vitro and in silico methods. The essential oil was extracted by Clevenger apparatus. Extracts were prepared by maceration for 72 hours. The Ellman's test was used to measure the inhibitory effects of the samples. The interaction of the main constituents of the essential oil with AChE was investigated by Coarse Grained molecular dynamics (CG‐MD) simulation. Essential oil inhibited the AChE with IC50: 44.6 μg/ml. Among different extracts, hydroalcoholic extract with IC50: 41.4 μg/ml exhibited the most potent inhibitory effect. Based on the results of 1 μs CG‐MD simulation, the major constituents of the essential oil inhibited the AChE by binding to the PAS site. The constituents of F. haussknechtii could be considered as a rich source for discovering and designing new AChE inhibitors. [ABSTRACT FROM AUTHOR]

The cattle tick Rhipicephalus (Boophilus) microplus is a major problem of concern for cattle industry in tropical and subtropical areas. Control of cattle tick is based mainly on the use of chemical acaricides, which has contributed to the emerging problem of selection of resistant tick lineages. Plants have been used as an alternative to conventional acaricidal drugs. On the other hand, the acaricidal activity of hydroethanolic extract of Randia aculeata seed (EHRA) has been demonstrated against R. microplus under laboratory conditions. However, the utility of EHRA seed as a potential acaricidal needs to be determined under field conditions. For this reason, the aim of this study was to evaluate the efficacy of the EHRA against R. microplus sprayed on naturally infested calves, determine the effect of the EHRA seed on acetylcholinesterase activity in R. microplus larval and identify the chemical composition of EHRA. Forty-five male calves were divided in three groups and treated with: G1 water; G2 EHRA 20% w/v and G3 coumaphos 0.2% v/v. Acetylcholinesterase (AChE) activity in R. microplus larvae was determined by a colorimetric assay. The chemical composition of EHRA was accessed through HPLC/MS. Significantly fewer ticks were observed after 24 h on the treated group compared to control group. EHRA significantly inhibited in vitro AChE activity in R. microplus at all tested concentrations. Chlorogenic acid, vanillinic acid, p-coumaric acid, caffeic acid. rutin, quercetin, (-)-epicatechin, 4-hydroxybenzoic acid, quercetin, vanillin, 2,4-dimethoxy-6-methylbenzoic acid, scopoletin and ferulic acid were identified in the extract. The results provided new data for the elucidation of the mechanisms of EHRA acaricide action and to further evaluate the use as a new alternative control agent against R. microplus under in vivo conditions. [ABSTRACT FROM AUTHOR]

Seaweeds have gained interest from the pharmaceutical industry due to their diverse secondary metabolites with potential applications in the prevention and treatment of lifestyle diseases. In spite of the abundance of seaweeds in the coastal area of Iligan Bay in the Philippines, there has been limited investigation into their pharmacological properties. Therefore, this study aimed to evaluate the in vitro α-glucosidase inhibition, angiotensin-converting enzyme (ACE) inhibition, and acetylcholinesterase (AChE) inhibition properties of various fractions obtained from the marine red alga Galaxaura oblongata. The methanol extract of G. oblongata was sequentially partitioned into hexane, dichloromethane, ethyl acetate, butanol, and methanol fractions. All assays were performed in vitro and microplate based. The results of α-glucosidase inhibition activity assay showed that the n-hexane fraction and dichloromethane fraction exhibited greater than 50% inhibitory activity at 200 ppm. Furthermore, ACE inhibition activity assay revealed that dichloromethane fraction, ethyl acetate fraction, and butanol fraction displayed ACE inhibition activity above 50% at 250 ppm. In addition, the hexane fraction, dichloromethane fraction, and ethyl acetate fraction demonstrated potent AChE inhibitory activity at 250 ppm. Overall, the findings show that G. oblongata has antidiabetic, anti-hypertensive, and neuroprotective potentials. This is the first report of the in vitro α-Glucosidase, ACE, and AChE inhibition activities of G. oblongata. Further investigation and purification of the highly potent fractions in each assay is highly suggested to identify and characterize the compounds responsible for the observed bioactivities, which could serve as possible leads for drug discovery efforts in the management of various lifestyle diseases [ABSTRACT FROM AUTHOR]

Loss of cerebral cholinergic neurons and decreased levels of acetylcholine (ACh) are considered to be major factors causing cognitive dysfunction in Alzheimer’s disease (AD). Abnormally elevated levels of acetylcholinesterase (AChE) resulting in decreased levels of ACh are common in AD patients; thus, AChE inhibitors (AChEIs) are widely used for the treatment of AD. In our previous work, we acquired DNA aptamers Ob1, Ob2, and Ob3 against human brain AChE from systematic evolution of ligands by exponential enrichment (SELEX). In this study, we investigated the effect of these aptamers on learning and memory abilities, as well as the underlying mechanism in a 5×FAD transgenic AD mouse model. Here, we showed that only aptamer Ob2 exhibits a good inhibitory effect on both mouse and human AChE activity. In addition, chronic treatment with aptamer Ob2 significantly improved cognitive ability of 5×FAD mice in the Morris water maze. Moreover, the mechanism of aptamer Ob2 in 5×FAD mice may be associated with its inhibition of AChE activity, alleviation of the levels of Aβ by lowering the expression of β-secretase (BACE1), and activation of astrocytes in the brains of 5×FAD mice. These results indicate that aptamer Ob2 exhibits potential as an effective AChEI for the treatment of AD.

The circadian rhythm is one of the most general and important rhythms in biological organisms. In this study, continuous 24-h video recordings showed that the cumulative movement distance and duration of the abalone, Haliotis discus hannai, reached their maximum values between 20:00–00:00, but both were significantly lower between 08:00–12:00 than at any other time of day or night (P 0.05). Following the injection of three different concentrations of neostigmine methylsulfate, as an AchE inhibitor, the concentration of Ach in the hemolymph, and the expression levels of nAchR in the cerebral ganglia increased significantly (P

Background and Objectives Diamond back moth, Plutella xylostella L. (Lepidoptera, Plutellidae), is the cosmopolite insect pest of cruciferous plants causing significant injury to the plants of this family. Although many integrated approaches have been proposed and developed for DBM management, the most common method of controlling this pest is chemical control. Organophosphates (OPs) are mainly used to control the agricultural pests in Iran, especially DBM. This study was performed to determine and compare some toxicological and biochemical properties of detoxification enzymes (ESTs and GST) and cholinesterase between two resistant (Esf-R) and susceptible (Ard-S) field populations of P. xylostella. Materials and Methods The phosalone-susceptible (Ard-S) population was collected from Ardabil, Ardabil province, Iran and the phosalone -resistant (Esf-R) population from Esfehan, Esfehan province, Iran. The toxicity of insecticides was measured using a standard leaf-dip bioassay. To determine the role of metabolic degradation as a mechanism for phosalone resistance in DBM, PBO (piperonyl butoxide), TPP (triphenyl phosphate) and DEM (diethyl maleate) were bioassayed for synergistic activity with phosalone (Kodwo and Tanaka, 2005). EST and GST assays were determined based on the method of Van Asperen (1962) and Habig et al. (1974) with minor modifications. AChE activity and its kinetic parameters were measured with two artificial substrates, ATC and BTC, along with the modified method of Ellman et al. (1961). Statistical analyses were evaluated by LeOra software (1978) through ANOVA followed by Tukey test. Results According to the bioassay results, the (Esf-R) population showed a significantly high resistance to phosalone compared with Ard-S population (17-fold). Diethyl maleate (DEM) and triphenyl phosphate (TPP), as glutathione S-transferase (GST) and esterase inhibitors, increased phosalon toxicity on both resistant and susceptible populations, but the synergistic ratio in the resistant population was higher than that of susceptible one. This confirms the greater role of esterase and GST enzymes in phosalone resistance. Metabolic resistance mechanisms to phosalone were surveyed by biochemical assays. The results indicated that specific activities (SA) of GST, α-esterase and ß-esterase were 2.1-, 2- and 1.7-fold higher in the resistant populations than those of susceptible population, suggesting higher expression of GST and esterase enzymes in resistant population. Furthermore, target site insensitivity was surveyed by biochemical assay. Kinetic parameters of acetylcholinesterase (AChE) on the hydrolysis of acetylthiocholine iodide (ATC) showed no change in the affinity of AChE of resistant population to this substrate and the phosalone resistance mechanism was not related to altered AChE active site. Conclusion The results distinctly indicated that metabolic detoxification mechanisms such as GST, esterases created phosalone resistance in the Esf-R and AChE structure were not involved in resistance. According to the result, use of synergists can be helpful for suppressing the phosalone resistance. [ABSTRACT FROM AUTHOR]

New mononuclear ternary transition metal complexes: [M(HL)(bipy)2]ClO4, (M: Mn(II) for 1, Ni(II) for 2), [M(HL) (bipy) (ClO4)], (M: Ni(II) for 3, Cu(II) for 4, Zn(II) for 5) with M(II), 2-[(hydroxyimino)methyl]-4-[-phenyldiazenyl] phenol, H2L, and 2,2'-bipyridine were synthesized, and their structures were investigated by using various analytical, spectroscopic techniques such as elemental analysis, FTIR, UV-Vis, NMR, MALDI-TOF mass spectrometry, thermal analysis. The theoretical studies were performed by DFT techniques by using B3LYP function with 6-311++G (d, p)/LanLD2Z basis set. The electronic transitions charters of the complexes were further analyzed by TD-DFT/CAM-B3LYP method. IR and thermal analysis data verify the proposed structures. The inhibition activities of the complexes against acetylcholinesterase (AChE) extracted from Ricania simulans adults and nymphs were examined and all the complexes were found to be active. Among the complexes studied, the highest inhibition activity was exhibited by complex 5 with the lowest IC50 value (3.2 ± 0.8 µM) for AChE of adults and complex 3 with the lowest IC50 value (4.6 ± 0.8 µM) for AChE of nymphs. [ABSTRACT FROM AUTHOR]

Biotransformations of stemofoline (1a), (2′S)-hydroxystemofoline (2a), (11Z)-1′,2′-didehydrostemofoline (3a) and stemocurtisine (4) were studied through fermentation with Cunninghamella elegans TISTR 3370. Three new stemofoline derivatives; (6 R)-hydroxystemofoline (1b), (2′S, 6 R)-dihydroxystemofoline (2b) and (11Z,6R)-1′,2′-didehydro-6-hydroxystemofoline (3b), together with the known compound 1′,2′-didehydrostemofoline-N-oxide (3c), were produced by C-hydroxylation and N-oxidation reactions. Stemocurtisine was not biotransformed under these conditions. The transformed product 1b was four times more potent (IC50 = 11.01 ± 1.49 µM) than its precursor 1a (IC50 = 45.1 ± 5.46 µM) as an inhibitor against acetylcholinesterase.

The secondary metabolites of Phaeosphaeria sp. LF5, an endophytic fungus with acetylcholinesterase (AChE) inhibitory activity isolated from Huperzia serrata, were investigated. Their structures and absolute configurations were elucidated by means of extensive spectroscopic data, including one- and two-dimensional nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) analyses, and calculations of electronic circular dichroism (ECD). A chemical study on the solid-cultured fungus LF5 resulted in 11 polyketide derivatives, which included three previously undescribed derivatives: aspilactonol I (4), 2-(1-hydroxyethyl)-6-methylisonicotinic acid (7), and 6,8-dihydroxy-3-(1′R, 2′R-dihydroxypropyl)-isocoumarin (9), and two new natural-source-derived aspilactonols (G, H) (2, 3). Moreover, the absolute configuration of de-O-methyldiaporthin (11) was identified for the first time. Compounds 4 and 11 exhibited inhibitory activity against AChE with half maximal inhibitory concentration (IC50) values of 6.26 and 21.18 µM, respectively. Aspilactonol I (4) is the first reported furanone AChE inhibitor (AChEI). The results indicated that Phaeosphaeria is a good source of polyketide derivatives. This study identified intriguing lead compounds for further research and development of new AChEIs. [ABSTRACT FROM AUTHOR]

Biotransformations of stemofoline (1a), (2′S)-hydroxystemofoline (2a), (11Z)-1′,2′-didehydrostemofoline (3a) and stemocurtisine (4) were studied through fermentation with Cunninghamella elegans TISTR 3370. Three new stemofoline derivatives; (6 R)-hydroxystemofoline (1b), (2′S, 6 R)-dihydroxystemofoline (2b) and (11Z,6R)-1′,2′-didehydro-6-hydroxystemofoline (3b), together with the known compound 1′,2′-didehydrostemofoline-N-oxide (3c), were produced by C-hydroxylation and N-oxidation reactions. Stemocurtisine was not biotransformed under these conditions. The transformed product 1b was four times more potent (IC50 = 11.01 ± 1.49 µM) than its precursor 1a (IC50 = 45.1 ± 5.46 µM) as an inhibitor against acetylcholinesterase. [ABSTRACT FROM AUTHOR]

The search for effective yet environmentally friendly strategies to prevent marine biofouling is hampered by the large taxonomic diversity amongst fouling organisms and a lack of well-defined conserved molecular targets. The acetylcholinesterase enzyme catalyses the breakdown of the neurotransmitter acetylcholine, and several natural antifouling allelochemicals have been reported to display acetylcholinesterase inhibitory activity. Our study is focussed on establishing if acetylcholinesterase can be used as a well-defined molecular target to accelerate discovery and development of novel antifoulants via sequential high-throughput in silico screening, in vitro enzymatic studies of identified compound libraries, and in vivo assessment of the most promising lead compounds. Using this approach, we identified potent cholinesterase inhibitors with inhibitory concentrations down to 3 μM from a 10,000 compound library. The most potent inhibitors were screened against five microfouling marine bacteria and marine microalgae and the macrofouling tunicate Ciona savignyi. No activity was seen against the microfoulers but a potent novel inhibitor of tunicate settlement and metamorphosis was discovered. Although only one of the identified active cholinesterase inhibitors displayed antifouling activity suggesting the link between cholinesterase inhibition and antifouling is limited to certain compound classes, the study highlights how in silico screening employed regularly for drug discovery can also facilitate discovery of antifouling leads.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease caused by neural cell death, characterized by the overexpression of acetylcholinesterase (AChE) and extracellular deposition of amyloid plaques. Currently, most of the FDA-approved AChE-targeting drugs can only relieve AD symptoms. There is no proven treatment capable to stop AD progression. Many natural products are isolated from several sources and analyzed through preclinical and clinical trials for their neuroprotective effects in preventing and treating AD. Therefore, this study aims to explore and determine potential candidates from natural bioactive compounds and their derivatives for AD treatment targeting AChE. In this study, feature extraction was carried out on 1730 compounds from six plants resulting from literature studies with limitations on international journals with a minimum publication year of 2018 and database searches, then classified using machine learning algorithms: Random Forest (RF), Logistic Regression (LR), and Support Vector Machine (SVM). Hit compounds predicted to be active and inactive in the selected model were then processed through ensemble modelling. From 1730 compounds, there are 986 predicted active compounds and 370 predicted inactive compounds in the LR and RF ensemble modelling. Quercetin, Kaempferol, Luteolin, Limonene, γ-Terpinene, Nerolidol, and Linalool predicted active found overlapping in two to three plants in both LR and RF models.

Left ventricular hypertrophy (LVH) is a major adaptative response to the increase in the overload produced by hypertension, is a risk factor for myocardial infarction, stroke, and heart failure. Among the several factors involved in hypertension and in the progression to cardiac hypertrophy, the hyperactivity of the renin–angiotensin system (RAS) and the dysfunction of the neurovisceral/autonomic nervous system are the main mechanisms involved. Evidence demonstrates that the inhibition of RAS and the increase in parasympathetic activity reduce significantly LVH ameliorating cardiac function. The development of multi-target compounds is a relevant strategy for treating hypertension and cardiac hypertrophy. This study aimed to synthesize three phthalamide derivatives (M-01, M-02, and M-03) and evaluate them as three-target (ACE/AChE/BuChE) inhibitors with the possible dual effect of reducing hypertension and reverting cardiac hypertrophy. After in silico and in vitro experiments, one compound was tested in vivo on rats. All three phthalamides were synthesized in good yields, showing good competitive inhibition of the three-target enzymes in silico and in vitro. M-01 (10 mg/kg) significantly reversed cardiomyocite hypertrophy (by 87.3%; p < 0.001) in the heart of spontaneous hypertensive rat (SHR) model. It was at least 18-fold more potent than the reference drug (captopril), which provided only 32.7% reversion. Three-target inhibitory activity was herein demonstrated for M-01, M-02, and M-03 in vitro and in silico, each with a similar effect. The compound tested in vivo (M-01) exhibited great potency in reducing hypertension and reverting cardiomyocyte hypertrophy, making it a promising candidate for further research. Highlights: The phthalamide derivatives are three-target inhibitors, acting on ACE, AChE, and BuChE. The test compounds showed potency in treating hypertension and reverting cardiomyocyte hypertrophy. M-01 was 18-fold more potent than captopril in reversing cardiomyocyte hypertrophy. [ABSTRACT FROM AUTHOR]

Background: Systemic arterial hypertension is a serious chronic health problem caused by multiple factors. It is a major risk factor for Cardiovascular Diseases (CVDs), including heart failure, coronary heart disease, and myocardial infarction. Hypertension can be effectively treated with inhibitors of the Angiotensin Converting Enzyme (ACE), such as captopril, enalapril, and lisinopril. However, these drugs are associated with significant adverse reactions (e.g., persistent coughing, skin rashes, and angioedema)., Objective: Considering the recent insights obtained by our group into the antihypertensive effect of boroxazolidones, the aim of the current contribution was to design and synthesize a series of these compounds derived from α-amino acids and evaluate them (in silico and in vitro) as inhibitors of ACE and acetylcholinesterase (AChE)., Methods: The best candidates were examined for their in vivo antihypertensive activity to regulate high blood pressure in male spontaneously hypertensive rats. Although boron-containing compounds were once thought to be toxic in any medical context, they have increasingly been used as antibiotics, antiseptics, and antineoplastic agents. BXZHis, BXZ-Lys, BXZ-Orn, BXZ-Phe, and BXZ-Pro were selected in silico as promising ACE and AChE inhibitors. After synthesis, these molecules were tested in vitro as ACE and AChE inhibitors, finding that most were effective at micromolar concentrations. The two best candidates, BXZ-Lys and BXZ-His, were evaluated in vivo with spontaneously hypertensive rats., Results: BXZ-Lys significantly decreased systolic, diastolic, and mean blood pressure, being more potent than a common ACE inhibitor, captopril., Conclusion: Future research is required to elucidate the mechanism of action of this antihypertensive effect., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Abstract Background Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative brain disorder, which is the most common form of dementia. Intensive efforts have been made to find effective and safe treatment against AD. Acetylcholinesterase inhibitors (AChEIs) have been widely used for the treatment of mild to moderate AD. In this study, we investigated the effect of Bis(9)-(−)-Meptazinol (B9M), a novel potential dual-binding acetylcholinesterase (AChE) inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD. Methods B9M (0.1 μg/kg, 0.3 μg/kg, and 1 μg/kg) was administered by subcutaneous injection into eight-month-old APP/PS1 transgenic mice for four weeks. Morris water maze, nest-building and novel object recognition were used to examine learning and memory ability. Aβ levels and Aβ plaque were evaluated by ELISA and immunochemistry. Results Our results showed that chronic treatment with B9M significantly improved the cognitive function of APP/PS1 transgenic mice in the Morris water maze test, nest-building test and novel object recognition test. Moreover, B9M improved cognitive deficits in APP/PS1 mice by a mechanism that may be associated with its inhibition of the AChE activity, Aβ plaque burden, levels of Aβ and the consequent activation of astrocytes and microglia in the brain of APP/PS1 transgenic mice. Most of important, the most effective dose of B9M in the present study is 1 μg/kg, which is one thousand of the dosage of Donepezil acted as the control treatment. Furthermore, B9M reduced Aβ plaque burden better than Donepezil. Conclusion These results indicate that B9M appears to have potential as an effective AChE inhibitor for the treatment of AD with symptom-relieving and disease-modifying properties.

Abstract Dioxoisoindolines have been included as a pharmacophore group in diverse drug-like molecules with a wide range of biological activity. Various reports have shown that phthalimide derivatives are potent inhibitors of AChE, a key enzyme involved in the deterioration of the cholinergic system during the development of Alzheimer’s disease. In the present study, 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione was synthesized, crystallized and evaluated as an AChE inhibitor. The geometric structure of the crystal and the theoretical compound (from molecular modeling) were analyzed and compared, finding a close correlation. The formation of the C6–H6···O19 interaction could be responsible for the non-negligible out of phenyl plane deviation of the C19 methoxy group, the O3 from the carbonyl group lead to C16–H16···O3i intermolecular interactions to furnish C(9) and C(14) infinite chains within the (− 4 0 9) and (− 3 1 1) families of planes. Finally, the biological experiments reveal that the isoindoline-1,3-dione exerts a good competitive inhibition on AChE (Ki = 0.33–0.93 mM; 95% confidence interval) and has very low acute toxicity (LD50 > 1600 mg/kg) compared to the AChE inhibitors currently approved for clinical use.

The discovery of acetylcholinesterase inhibitors is important for the treatment of Alzheimer's disease (AD), known as the most common type of dementia. Due to the side effects of commonly used acetylcholinesterase inhibitors, studies for the detection of new inhibitors are increasing day by day. In this study, we investigated the effects of some sulfonamide derivatives (S1–S4 and S1i–S4i) on AChE enzymes. The best pose of the active compounds to understand the mechanism of possible inhibition in interaction of enzyme-sulfonamide derivative were performed docking studies after in vitro experimental results. ADME-related physicochemical and pharmacokinetic properties of the synthesized 4-aminobenzenesulfonamide derivatives were the compatibility with Lipinski's rule of five. We found that the synthesized derivatives of sulfonamides show potential inhibitor properties for AChE with Ki constants in the range of 2.54 ± 0.22–299.60 ± 8.73 µM. The derivatives of sulfonamides exhibited different inhibition type. We determined that the derivatives (S1, S1i, S3, and S3i) showed a competitive inhibition effect, whereas others (S2, S2i, S4, and S4i) showed mixed-type inhibition. As a result, the sulfonamide derivatives can be used as an alternative acetylcholinesterase inhibitor due to this effect. Inhibitors with fewer side effects, are thought to be important in the treatment of AD. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is by far the most prevalent of all known forms of dementia. Despite wide-spread research, the main causes of emergence and development of AD have not been fully recognized. Natural, low-molecular, lipophilic terpenoids constitute an interesting group of secondary plant metabolites, that exert biological activities of possible use in the prevention and treatment of AD. In order to identify secondary metabolites possessing both antioxidant activity and the potential to increase the level of acetylcholine, selected terpenoids have been screened for possible acetylcholinesterase inhibitory activity by use of two methods, namely Marston (chromatographic assay) and Ellman (spectrophotometric assay). In order to describe the interaction between terpenes and AChE active gorge, molecular docking simulations were performed. Additionally, all analyzed terpenes were also evaluated for their cytotoxic properties against two normal cell lines using MTT assay. The obtained results show that: carvone (6), pulegone (8) and γ-terpinene (7) possess desirable AChE inhibitory activity. MTT assay revealed low or lack of cytotoxicity of these metabolites. Thus, among the investigated terpenes, carvone (6), pulegone (8) and y-terpinene (7) can be recognized as compounds with most promising activities in the development of multi-target directed ligands.

Background: The exact mechanisms involved in the pathogenesis of neurodegenerative conditions are not fully known. The design of drugs that act on multiple targets represents a promising approach that should be explored for more effective clinical options for neurodegenerative disorders. B7C is s synthetic drug that has been studied for over 20 years and represents a promising multi-target drug for the treatment of neurodegenerative disorders, such as AD.Aims: The present systematic review, thus, aims at examining existing studies on the effect of B7C on different molecular targets and at discussing the relevance of B7C in neurological disorders.Methods: A list of predefined search terms was used to retrieve relevant articles from the databases of Embase, Pubmed, Scopus, and Web of Science. The selection of articles was done by two independent authors, who were considering articles concerned primarily with the evaluation of the effect of B7C on neurological disorders. Only full-text articles written in English were included; whereas, systematic reviews, meta-analyses, book chapters, conference subtracts, and computational studies were excluded.Results: A total of 2,266 articles were retrieved out of which 41 articles were included in the present systematic review. The effect of B7C on molecular targets, including AChE, BChE, BACE-1, NMDA receptor, GABA receptor, NOS, and Kv4.2 potassium channels was evaluated. Moreover, the studies that were included assessed the effect of B7C on biological processes, such as apoptosis, neuritogenesis, and amyloid beta aggregation. The animal studies examined in the review focused on the effect of B7C on cognition and memory.Conclusions: The beneficial effects observed on different molecular targets and biological processes relevant to neurological conditions confirm that B7C is a promising multi-target drug with the potential to treat neurological disorders.

Background: The exact mechanisms involved in the pathogenesis of neurodegenerative conditions are not fully known. The design of drugs that act on multiple targets represents a promising approach that should be explored for more effective clinical options for neurodegenerative disorders. B7C is s synthetic drug that has been studied for over 20 years and represents a promising multi-target drug for the treatment of neurodegenerative disorders, such as AD. Aims: The present systematic review, thus, aims at examining existing studies on the effect of B7C on different molecular targets and at discussing the relevance of B7C in neurological disorders. Methods: A list of predefined search terms was used to retrieve relevant articles from the databases of Embase, Pubmed, Scopus, and Web of Science. The selection of articles was done by two independent authors, who were considering articles concerned primarily with the evaluation of the effect of B7C on neurological disorders. Only full-text articles written in English were included; whereas, systematic reviews, meta-analyses, book chapters, conference subtracts, and computational studies were excluded. Results: A total of 2,266 articles were retrieved out of which 41 articles were included in the present systematic review. The effect of B7C on molecular targets, including AChE, BChE, BACE-1, NMDA receptor, GABA receptor, NOS, and Kv4.2 potassium channels was evaluated. Moreover, the studies that were included assessed the effect of B7C on biological processes, such as apoptosis, neuritogenesis, and amyloid beta aggregation. The animal studies examined in the review focused on the effect of B7C on cognition and memory. Conclusions: The beneficial effects observed on different molecular targets and biological processes relevant to neurological conditions confirm that B7C is a promising multi-target drug with the potential to treat neurological disorders. [ABSTRACT FROM AUTHOR]

Although the mechanism of Alzheimer's disease (AD) is still not fully understood, the development of multifunctional AChE inhibitors remains a research focus for AD treatment. In this study, 48 AChE candidate inhibitors were picked out from SPECS database through a pharmacophore- and molecular docking-based virtual screening. The biological evaluation results indicated that four compounds 7, 29, 41 and 48 with different scaffolds exhibited potent and selective AChE inhibitory activity, with the best IC50 value of 1.62 ± 0.11 μM obtained for 48. Then their mechanism of action, the inhibition on Aβ aggregation, neurotoxicity, and neuroprotective activity against Aβ-induced nerve cell injury were well studied. The binding mode of 48 with AChE was also proposed. The present bioassay results indicated that these multifunctional AChE inhibitors were worth for further structural derivatization to make them the anti-AD lead compounds. [ABSTRACT FROM AUTHOR]

A library of 22 derivatives of 1,3,4-oxadiazole-2-thiol was synthesized, structurally characterized, and assessed for its potential to inhibit α-amylase, α-glucosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and antioxidant activities. Most of the tested compounds demonstrated good to moderate inhibition potential; however, their activity was lower than that of the standard acarbose. Significantly, compound 3f exhibited the highest inhibition potential against α-glucosidase and α-amylase enzymes, with IC 50 values of 18.52 ± 0.09 and 20.25 ± 1.05 µM, respectively, in comparison to the standard acarbose (12.29 ± 0.26; 15.98 ± 0.14 µM). Compounds also demonstrated varying degrees of inhibitory potential against AChE (IC 50  = 9.25 ± 0.19 to 36.15 ± 0.12 µM) and BChE (IC 50  = 10.06 ± 0.43 to 35.13 ± 0.12 µM) enzymes compared to the standard donepezil (IC 50  = 2.01 ± 0.12; 3.12 ± 0.06 µM), as well as DPPH (IC 50  = 20.98 ± 0.06 to 52.83 ± 0.12 µM) and ABTS radical scavenging activities (IC 50  = 22.29 ± 0.18 to 47.98 ± 0.03 µM) in comparison to the standard ascorbic acid (IC 50  = 18.12 ± 0.15; 19.19 ± 0.72). The kinetic investigations have demonstrated that the compounds exhibit competitive-type inhibition for α-amylase, noncompetitive-type inhibition for α-glucosidase and AChE, and mixed-type inhibition for BChE. Additionally, a molecular docking study was performed on all synthetic oxadiazoles to explore the interaction details of these compounds with the active sites of the enzymes., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

Alzheimer's disease (AD) is a complex neurodegenerative disorder involving cognitive dysfunction like short-term memory and behavioral changes as the disease progresses due to other unaltered physiological factors. The solution for this problem is Multi-targeted Drugs (MTDs), which can affect multiple determinants to realize the multifunctional effects. Acetylcholinesterase (AChE) inhibitors donepezil, rivastigmine, galantamine, and N-methyl-D-aspartate (NMDA) receptor antagonist memantine are FDA-approved drugs used to treat AD symptomatically. The key objective of this review is to understand multitargeted bioactive natural molecules that could be considered as leads for further development as effective drugs for treating AD, along with understanding its pharmacology and structure-activity relationship (SAR). Understanding the molecular mechanism of the AD pathophysiology, the role of existing drugs, treatment of AD via amyloid beta (Aβ) plaque, and neurofibrillary tangle (NFT) inhibition by natural bioactive molecules were also discussed in the review. The current quest and recent advancements with natural bioactive compounds like physostigmine, resveratrol, curcumin, and catechins, along with the study of in silico SAR, were reported in the present study. This review summarises the structural properties required for bioactive natural molecules to show anti-Alzheimer's activity by emphasizing on SAR of several bioactive natural molecules targeting various AD pathologies, their key molecular interactions that are critical for target specificity, their role as multitargeted ligands, used with adjunctive therapy for AD followed by related US patents granted recently. This article highlights the significance of the structural features of natural bioactive molecules in the treatment of AD and establishes a connection between them.Communicated by Ramaswamy H. Sarma.

Introduction: Previous studies have demonstrated that several ginsenosides have remarkable inhibitory effect on acetylcholinesterase (AChE). In the present study, ginseng stem–leaf saponins (GSLS) can improve learning and memory of Alzheimer's disease patients. However, much comprehensive information regarding AChE inhibition of GSLS and its metabolites is yet unknown. Objective: The present study aims to screen and determine the potential of AChE inhibitors (AChEIs) from GSLS. Methodology: The active fraction of the GSLS detected in vitro AChE inhibition assays was selected as a starting material for the screening of the potential of AChEIs using ultrafiltration liquid chromatography coupled to electrospray ionisation tandem mass spectrometry (UF‐LC‐ESI‐MS2). Results: The results showed that 31 ginsenosides were identified with analysis using rapid resolution liquid chromatography with a diode array detector combined with electrospray ionisation tandem mass spectrometry (RRLC‐DAD‐ESI‐MS2) from the active fraction, and there are 27 compounds with AChE binding activity. Among them, 11 ginsenosides were evaluated and confirmed using in vitro enzymatic assay, and ginsenosides F1, Rd, Rk3, 20(S)‐Rg3, F2 and Rb2 were found to possess strong AChE inhibitory activities. Conclusion: The proposed UF‐LC‐ESI‐MS2 method was a powerful tool for the discovery of AChEIs from traditional Chinese medicine (TCM). A total of 31 compounds in Fr.5 were characterised and identified with the proposed RRLC‐DAD‐ESI‐MS2. Six ginsenosedes,F1, Rd, Rk3, 20(S)‐Rg3, F2 and Rb2, were found to have potential AChEI activity and were confirmed by the in vitro enzyme experiments. Among them, ginsenosede F1, Rk3 and F2 were firstly studied and found their AChE inhibitiory activities. The obtained results are expected to be valuable for discovering AChEIs from GSLS and efficiently designing drugs for the prevention and treatment of AD. [ABSTRACT FROM AUTHOR]

Two new triterpenoids, named kadsuricoccins A and B, together with three known ones, were isolated from the Li folk herb Heilaohu, the stems of Kadsura coccinea (Lem.) A. C. Smith, which was used for food and as a healthy supplement. Their structures were elucidated by comprehensive analyses of mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopic data. To search healthy components, an acetylcholinesterase (AChE) inhibitory activity test by Ellman’s Method was conducted, kadsuricoccins A and B showed activity with the AChE inhibit index (AII) up to 68.96% ± 0.19% and 57.8% ± 0.11% at 94 nM (compared with positive control tacrine AII 79.80% ± 0.20%, 9.4 nM), respectively.

Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to symptomatic treatment, and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Since the therapeutic paradigm “one compound−one-target” has shown its limits in the treatment of AD, new strategies are emerging to overcome the lack of efficiency of the current pharmacotherapy in the past decade. The most promising is the multitarget-directed ligands (MTDLs) strategy. This project consists of the development of new multifunctional agents, which will act simultaneously on the different players in AD pathology by combining an AChE inhibitory activity based on the structures of a well-known AChE inhibitor (Rivastigmine) with an α-7 nAChR activation. Indeed, nAChRs were recently put forward as potential targets for the treatment of central nervous system (CNS) diseases, such as AD. Because of their distribution and abundance in the CNS, the α-7 subtypes are potential therapeutic targets for this disorder.

Alzheimer's disease (AD) is the most common form of dementia worldwide with an increasing prevalence for the next years. The multifactorial nature of AD precludes the design of new drugs directed to a single target being probably one of the reasons for recent failures. Therefore, dual binding site acetylcholinesterase (AChE) inhibitors have been revealed as cognitive enhancers and β-amyloid modulators offering an alternative in AD therapy field. Based on the dual ligands NP61 and donepezil, the present study reports the synthesis of a series of indolylpiperidines hybrids to optimize the NP61 structure preserving the indole nucleus, but replacing the tacrine moiety of NP61 by benzyl piperidine core found in donepezil. Surprisingly, this new family of indolylpiperidines derivatives showed very potent and selective h BuChE inhibition. Further studies of NMR and molecular dynamics have showed the capacity of these hybrid molecules to change their bioactive conformation depending on the binding site, being capable to inhibit with different shapes BuChE and residually AChE. [ABSTRACT FROM AUTHOR]

Polyfunctional compounds comprise a novel class of therapeutic agents for the treatment of multi-factorial diseases. A series of 2-Phenyl-4H-chromen-4-one and its derivatives (5a–n) were designed, synthesized, and evaluated for their poly-functionality against acetylcholinestrase (AChE) and advanced glycation end products (AGEs) formation inhibitors against Alzheimer’s disease (AD). The screening results showed that most of them exhibited a significant ability to inhibit AChE AGEs formation with additional radical scavenging activity. Especially, 5m, 5b, and 5j displayed the greatest ability to inhibit AChE (IC50 = 8.0, 8.2, and 11.8 nM, respectively) and AGEs formation (IC50 = 55, 79, and 54 µM, respectively) with good antioxidant activity. Molecular docking studies explored the detailed interaction pattern with active, peripheral, and mid-gorge sites of AChE. These compounds, exhibiting such multiple pharmacological activities, can be further taken a lead for the development of potent drugs for the treatment of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer’s disease (AD). The results showed that compound TM - 9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B ( hu AChE, hu BuChE, and hu MAO-B with IC 50 values of 1.2 μM, 3.8 μM and 2.6 μM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM - 9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM - 9 abided by Lipinski’s rule of five. Furthermore, our investigation proved that TM - 9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro . The results suggest that compound TM - 9 , an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel 3,4-dihydro-2(1 H )-quinoline- O -alkylamine derivatives have been designed using a conjunctive approach that combines the JMC49 and donepezil. The most promising compound TM - 33 showed potent and balance inhibitory activities toward ChE and MAO (eeAChE, eqBuChE, hMAO-A and hMAO-B with IC 50 values of 0.56 μM, 2.3 μM, 0.3 μM and 1.4 μM, respectively) but low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM - 33 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Furthermore, our investigation proved that TM - 33 could cross the blood-brain barrier (BBB) in vitro , and abided by Lipinski’s rule of five. The results suggest that compound TM - 33 , an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Deficiency of the cholinergic system is thought to play a vital role in cognitive impairment of dementia. DL0410 was discovered as a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinestease (BuChE), with potent efficiency in in-vitro experiments, but its in vivo effect on the cholinergic model has not been evaluated, and its action mechanism has also not been illustrated. In the present study, the capability of DL0410 in ameliorating the amnesia induced by scopolamine was investigated, and its effect on the cholinergic system in the hippocampus and its binding mode in the active site of AChE was also explored. Mice were administrated DL0410 (3 mg/kg, 10 mg/kg, and 30 mg/kg), and mice treated with donepezil were used as a positive control. The Morris water maze, escape learning task, and passive avoidance task were used as behavioral tests. The test results indicated that DL0410 could significantly improve the learning and memory impairments induced by scopolamine, with 10 mg/kg performing best. Further, DL0410 inhibited the AChE activity and increased acetylcholine (ACh) levels in a dose-dependent manner, and interacted with the active site of AChE in a similar manner as donepezil. However, no difference in the activity of BuChE was found in this study. All of the evidence indicated that its AChE inhibition is an important mechanism in the anti-amnesia effect. In conclusion, DL0410 could be an effective therapeutic drug for the treatment of dementia, especially Alzheimer's disease. [ABSTRACT FROM AUTHOR]